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Chromosomes in eukaryotic cell nuclei are highly compacted and finely organized into hierarchical three-dimensional (3D) configuration. In recent years, scientists have gained deeper understandings of 3D genome structures and revealed novel evidence linking 3D genome organization to various important cell events on the molecular level. Most importantly, alteration of 3D genome architecture has emerged as an intriguing higher order mechanism that connects disease-related genetic variants in multiple heterogenous and polygenic neuropsychological disorders, delivering novel insights into the etiology. In this review, we provide a brief overview of the hierarchical structures of 3D genome and two proposed regulatory models, loop extrusion and phase separation. We then focus on recent Hi-C data in the central nervous system and discuss 3D genome alterations during normal brain development and in mature neurons. Most importantly, we make a comprehensive review on current knowledge and discuss the role of 3D genome in multiple neuropsychological disorders, including schizophrenia, repeat expansion disorders, 22q11 deletion syndrome, and others.

The 22q11 deletion syndrome is a genetic disorder associated with a high risk of developing psychosis, and is therefore considered a neurodevelopmental model for studying the pathogenesis of schizophrenia. Studies have shown that localized abnormal functional brain connectivity is present in 22q11 deletion syndrome like in schizophrenia. However, it is less clear whether these abnormal cortical interactions lead to global or regional network disorganization as seen in schizophrenia. We analyzed from a graph-theory perspective fMRI data from 40 22q11 deletion syndrome patients and 67 healthy controls, and reconstructed functional networks from 105 brain regions. Between-group differences were examined by evaluating edge-wise strength and graph theoretical metrics of local (weighted degree, nodal efficiency, nodal local efficiency) and global topological properties (modularity, local and global efficiency). Connectivity strength was globally reduced in patients, driven by a large network comprising 147 reduced connections. The 22q11 deletion syndrome network presented with abnormal local topological properties, with decreased local efficiency and reductions in weighted degree particularly in hub nodes. We found evidence for abnormal integration but intact segregation of the 22q11 deletion syndrome network. Results suggest that 22q11 deletion syndrome patients present with similar aberrant local network organization as seen in schizophrenia, and this network configuration might represent a vulnerability factor to psychosis.

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 & ndash;hippocampal & ndash;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.

Hyperprolinemia Type I and II are genetic metabolic disorders caused by disrupted proline degradation. It has been suggested that hyperprolinemia is associated with increased risk of developmental and mental disorders but detailed information on the psychiatric phenotype in hyperprolinemic patients is limited. Following PRISMA guidelines, we carried out a systematic review to clarify psychiatric phenotypes in patients with hyperprolinemia. We screened 1753 studies and included 35 for analysis, including 20 case reports and 15 case–control and cohort studies. From these studies, a common psychiatric phenotype is observed with a high prevalence of developmental delay, intellectual disability, autism spectrum disorders, and psychosis spectrum disorders. In most cases, a genetic cause of hyperprolinemia was known, these included mutations in the PRODH and ALDH4A1 genes and deletions of chromosome 22q11.2. No evidence for a biochemical phenotype-clinical phenotype correlation was found; that is, no association between higher proline levels and specific psychiatric phenotypes was observed. This suggests that genomic and environmental factors are likely to contribute to clinical outcomes. More studies are needed to clarify whether hyperprolinemia is a primary causal factor underlying the increased risk of developing psychiatric disorders seen in patients with hyperprolinemia, or whether hyperprolinemia and psychiatric disorders are both consequences of a shared underlying mechanism.

Item does not contain fulltext The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira(+/-) mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira(+/-) mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.

SUMMARY Congenital heart disease (CHD) is one of the most common combined malformations of microtia. There is currently no specific study that investigates the relationship between microtia and CHD. METHODS This study collected microtia inpatients admitted from May 1, 2015 to July 31, 2016. The diagnosis of CHD was based on patient's symptoms, past history, and echocardiography. Pearson χ2 test was used to analyze the correlation between CHD and microtia. RESULTS A total of 30 cases (3.35%) were documented with CHD, including atrial septal defect (12/40.00%), ventricular septal defect (7/23.30%), patent ductus arteriosus (2/6.70%), complex congenital heart disease (3/10.00%), combined CHD (2/6.70%) and other malformations (4/13.30%). Analysis showed no statistically significant relation between CHD and the side of affected ear or gender. CONCLUSIONS The occurrence of CHD in microtia patients was higher than that in the general population. The relationship between them was explored mainly from the etiological perspective. Microtia and CHD were often combined in syndromes such as Goldenhar syndrome, 22q11 deletion syndrome, and CHARGE syndrome. Absence of genes or abnormal embryo development associated with these syndromes leads to the occurrence of both.

The normal development of the heart comprises a highly regulated machinery of genetic events, involving transcriptional factors. Congenital heart disease (CHD), have been associated with chromosomal abnormalities and copy number variants (CNVs). Our goal was to investigate through the multiplex ligation-dependent probe amplification (MLPA) technique, the presence of CNVs in reference genes for normal cardiac development in patients with CHD. GATA4, NKX2–5, TBX5, BMP4, and CRELD1 genes and 22q11.2 chromosome region were analyzed in 207 children with CHD admitted for the first time in a cardiac intensive care unit from a pediatric hospital. CNVs were detected in seven patients (3.4%): four had a 22q11.2 deletion (22q11DS) (1.9%), two had a GATA4 deletion (1%) and one had a 22q11.2 duplication (0.5%). No patients with CNVs in the NKX2–5, TBX5, BMP4, and CRELD1 genes were identified. GATA4 deletions appear to be present in a significant number of CHD patients, especially those with septal defects, persistent left superior vena cava, pulmonary artery abnormalities, and extracardiac findings. GATA4 screening seems to be more effective when directed to these CHDs. The investigation of CNVs in GATA4 and 22q11 chromosome region in patients with CHD is important to anticipating the diagnosis, and to contributing to family planning.

OBJECTIVE The objective of this study was to identify patient and hospitalization characteristics associated with in-hospital mortality in infants with truncus arteriosus. METHODS We conducted a retrospective analysis of a large administrative database, the National Inpatient Sample data set of the Healthcare Cost and Utilization Project for the years 2002 to 2017. We also sought to evaluate the resource utilization in the subgroup of subjects with truncus arteriosus and 22q11.2 deletion syndrome. Neonates with truncus arteriosus were identified by ICD-9 and ICD-10 codes. Hospital and patient factors associated with inpatient mortality were analyzed. RESULTS Overall, 3009 neonates met inclusion criteria; a total of 326 patients died during the hospitalization (10.8%). Extracorporeal membrane oxygenation utilization was 7.1%. Univariate and multivariate logistic regression analyses were used to identify risk factors for in-hospital mortality. Significant risk factors for mortality were prematurity (adjusted odds ratio [aOR] = 2.43; 95% confidence interval [CI]: 1.40-4.22; P = .002), diagnosis of stroke (aOR = 26.2; 95% CI: 10.1-68.1; P

Ectopic calcification in soft tissue is associated with several disorders including pseudohypoparathyroidism (PHP), which is characterized by resistance or nonresponse to parathyroid hormone (PTH) function. Association between PHP and 22q11DS, also known as DiGeorge syndrome, is rare, especially in children. We describe a newborn girl diagnosed with 22q11DS, presenting ectopic calcifications in soft tissue and suspicion of PHP. PTH function showed values close to the upper limit of the reference value. Radiology showed bone callus in the right wrist. PHP can be a new clinical finding associated with 22q11DS. Parathyroid function investigation in individuals with 22q11DS, presenting bone dysmorphisms and/or calcium metabolism alterations, should be considered.

El síndrome de DiGeorge, también conocido como síndrome velocardiofacial o síndrome de deleción 22q11, se caracteriza por la ausencia congénita del timo y la glándula paratiroides. La tríada clásica de este trastorno es cardiopatía congénita, endocrinopatía con hipocalcemia e inmunodeficiencia primaria. Sin embargo, el síndrome puede exhibir múltiples alteraciones y manifestaciones clínicas pleiotrópicas que, a menudo, resultan en dismorfismo facial y alteraciones en el paladar. Clínicamente se evidencia mayor susceptibilidad a infecciones respiratorias o gastrointestinales recurrentes y, en los casos de aplasia tímica, se requiere tratamiento con antibióticos profilácticos y trasplante tímico, mientras que en los demás se hace manejo expectante. En este manuscrito se presenta el caso de un paciente masculino de 18 meses de edad, remitido al servicio de genética por presentar diversas alteraciones fenotípicas. Se describe el proceso mediante el cual se llegó al diagnóstico de síndrome de DiGeorge, a su manejo y pronóstico, y se hace una breve revisión de la literatura.

22q11.2 deletion syndrome is characterised by a well defined microdeletion that is associated with a high risk of neuropsychiatric disorders, including intellectual disability, schizophrenia, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety disorders, seizures and epilepsy, and early-onset Parkinson’s disease. Preclinical and clinical data reveal substantial variability of the neuropsychiatric phenotype despite the shared underlying deletion in this genetic model. Factors that might explain this variability include genetic background effects, additional rare pathogenic variants, and potential regulatory functions of some genes in the 22q11.2 deletion region. These factors might also be relevant to the pathophysiology of these neuropsychiatric disorders in the general population. We review studies that might provide insight into pathophysiological mechanisms underlying the expression of neuropsychiatric disorders in 22q11.2 deletion syndrome, and potential implications for these common disorders in the general (non-deleted) population. The recurrent hemizygous 22q11.2 deletion, associated with 22q11.2 deletion syndrome, has attracted attention as a genetic model for common neuropsychiatric disorders because of its association with substantially increased risk of such disorders.(1) Studying such a model has many advantages. First, 22q11.2 deletion has been genetically well characterised.(2) Second, most genes present in the region typically deleted at the 22q11.2 locus are expressed in the brain.(3–5) Third, genetic diagnosis might be made early in life, long before recognisable neuropsychiatric disorders have emerged. Thus, this genetic condition offers a unique opportunity for early intervention, and monitoring individuals with 22q11.2 deletion syndrome throughout life could provide important information on factors contributing to disease risk and protection. Despite the commonly deleted region being shared by about 90% of individuals with 22q11.2 deletion syndrome, neuropsychiatric outcomes are highly variable between individuals and across the lifespan. A clear link remains to be established between genotype and phenotype.(3,5) In this Review, we summarise preclinical and clinical studies investigating biological mechanisms in 22q11.2 deletion syndrome, with a focus on those that might provide insight into mechanisms underlying neuropsychiatric disorders in 22q11.2 deletion syndrome and in the general population.

Summary Congenital heart defects are a feature of several genetic haploinsufficiency syndromes, often involving transcriptional regulators. One property of haploinsufficient genes is their propensity for network interactions at the gene or protein level. In this article we took advantage of an online dataset of high throughput screening of mutations that are embryonic lethal in mice. Our aim was to identify new genes where the loss of function caused cardiovascular phenotypes resembling the 22q11.2 deletion syndrome models, that is, heterozygous and homozygous loss of Tbx1. One gene with a potentially haploinsufficient phenotype was identified, Setd5, thought to be involved in chromatin modification. We found murine Setd5 haploinsufficiency to be associated with double outlet right ventricle and perimembranous ventricular septal defect, although no genetic interaction with Tbx1 was detected. Conditional mutagenesis revealed that Setd5 was required in cardiopharyngeal mesoderm for progression of the heart tube through the ballooning stage to create a four‐chambered heart.

Rare pathogenic copy number variants (CNVs) are genetic rearrangements that have been associated with an increased risk for congenital heart disorders (CHDs). However, the association of CNVs with atypical brain development, leading to neurodevelopmental disorders (NDDs), in the presence of CHDs remains unclear. We attempted to explore this association by establishing the prevalence and burden of CNVs associated with CHD in a Welsh population and by studying the effect of rare CNVs associated with CHDs in mediating the risk of NDDs. Toward this goal, we analyzed data from the Congenital Anomaly Register for Wales (CARIS), referred from hospitals in Wales between 1998 and 2018, which included 1,113 subjects in total. Of these, 785 subjects were included in the study following application of the exclusion criteria, and a total of 28 rare CNVs associated with CHD were analyzed. The findings from this cohort study identified 22q11.2 deletion as the most prominent CNV across the cohort. Our data demonstrates that the survival rate of the cohort after 3 years was 99.9%, and mortality fell significantly between 1 and 2 years and between 2 and 3 years [F(1,27) = 10, p = 0.0027; F(1,27) = 5.8, p = 0.0222]. Importantly, the data set revealed a positive correlation between the incidence of congenital heart disease and the incidence of neurodevelopmental abnormalities in patients with CNVs across the whole cohort [95% CI (0.4062, 0.8449), p < 0.0001, r = 0.6829]. Additionally, we identified significant CNVs that result in the co-morbidity of CHD and NDD and show that septal defects and global developmental delay are major congenital defects. Further research should identify a common molecular mechanism leading to the phenotypic comorbidity of CHDs and NDDs, arising from a common CNV, which can have an implication for improving risk classification and for fetal neuroprotection strategies in the affected children and in precision medicine.

22q11.2 Deletion Syndrome (22q11DS) is a neurodevelopmental disorder associated with cranial nerve anomalies and disordered oropharyngeal function, including pediatric dysphagia. Using the LgDel 22q11DS mouse model, we investigated whether sensory neuron differentiation in the trigeminal ganglion (CNgV), which is essential for normal orofacial function, is disrupted. We did not detect changes in cranial placode cell translocation or neural crest migration at early stages of LgDel CNgV development. However, as the ganglion coalesces, proportions of placode-derived LgDel CNgV cells increase relative to neural crest cells. In addition, local aggregation of placode-derived cells increases and aggregation of neural crest-derived cells decreases in LgDel CNgV. This change in cell-cell relationships was accompanied by altered proliferation of placode-derived cells at embryonic day (E)9.5, and premature neurogenesis from neural crest-derived precursors, reflected by an increased frequency of asymmetric neurogenic divisions for neural crest-derived precursors by E10.5. These early differences in LgDel CNgV genesis prefigure changes in sensory neuron differentiation and gene expression by postnatal day 8, when early signs of cranial nerve dysfunction associated with pediatric dysphagia are observed in LgDel mice. Apparently, 22q11 deletion destabilizes CNgV sensory neuron genesis and differentiation by increasing variability in cell-cell interaction, proliferation and sensory neuron differentiation. This early developmental divergence and its consequences may contribute to oropharyngeal dysfunction, including suckling, feeding and swallowing disruptions at birth, and additional orofacial sensory/motor deficits throughout life., Summary: Altered proportions, distribution, timing and modes of division for trigeminal ganglion progenitors prefigure divergent trigeminal sensory neuron differentiation and oropharyngeal dysfunction in the LgDel mouse model of 22q11.2 deletion syndrome.

Background The neurobehavioral phenotype of 22q11.2 deletion syndrome (22q11DS) includes cognitive dysfunction and high rates of psychotic symptoms and schizophrenia. Existing research has mainly considered changes in IQ, especially its decline, as a psychosis predictor. The aim of this study was to investigate, in a longitudinal perspective, the relationship between neuropsychological abilities (not only IQ but also executive functioning, language and visual-motor integration abilities) and onset of psychotic symptoms in a sample of children, adolescents and young adults with 22q11DS. In addition, the role of comorbid psychiatric disorders at baseline was taken into account. Methods 75 participants with 22q11DS, aged between 6 and 27 years at baseline, were included. Eighteen of the 75 participants had developed psychosis at the one year follow-up (onset psychosis-OP) and constituted the first group; 57 participants who had not developed a psychosis at the one year follow-up (without onset psychosis-WOP) constituted the second group. Results At baseline, group OP showed lower IQ (both full scale and verbal and performance scale) and more perseverative errors as well as a reduced number of correct categories on the Wisconsin Card Sorting Test (WCST) compared to group WOP. In addition, at baseline, group OP showed a higher frequency of depressive disorders than group WOP. Conclusion Even if with caution, results suggest neuropsychological deficits and depressive symptoms should be considered and monitored as possible clinical signs for the onset of psychosis in children, adolescents and young adults with 22q11DS.

BackgroundYoung people with 22q11.2 deletion syndrome (22q11.2DS) are at high risk for neurodevelopmental disorders. Sleep problems may play a role in this risk but their prevalence, nature and links to psychopathology and cognitive function remain undescribed in this population.MethodSleep problems, psychopathology, developmental coordination and cognitive function were assessed in 140 young people with 22q11.2DS (mean age = 10.1, s.d. = 2.46) and 65 unaffected sibling controls (mean age = 10.8, s.d.SD = 2.26). Primary carers completed questionnaires screening for the children's developmental coordination and autism spectrum disorder.ResultsSleep problems were identified in 60% of young people with 22q11.2DS compared to 23% of sibling controls (OR 5.00, p < 0.001). Two patterns best-described sleep problems in 22q11.2DS: restless sleep and insomnia. Restless sleep was linked to increased ADHD symptoms (OR 1.16, p < 0.001) and impaired executive function (OR 0.975, p = 0.013). Both patterns were associated with elevated symptoms of anxiety disorder (restless sleep: OR 1.10, p = 0.006 and insomnia: OR 1.07, p = 0.045) and developmental coordination disorder (OR 0.968, p = 0.0023, and OR 0.955, p = 0.009). The insomnia pattern was also linked to elevated conduct disorder symptoms (OR 1.53, p = 0.020).ConclusionsClinicians and carers should be aware that sleep problems are common in 22q11.2DS and index psychiatric risk, cognitive deficits and motor coordination problems. Future studies should explore the physiology of sleep and the links with the neurodevelopment in these young people.

Background22q11.2 deletion syndrome (22q11DS), one of the most common recurrent copy number variant disorders, is associated with dopaminergic abnormalities and increased risk for psychotic disorders.AimsGiven the elevated prevalence of substance use and dopaminergic abnormalities in non-deleted patients with psychosis, we investigated the prevalence of substance use in 22q11DS, compared with that in non-deleted patients with psychosis and matched healthy controls.MethodThis cross-sectional study involved 434 patients with 22q11DS, 265 non-deleted patients with psychosis and 134 healthy controls. Psychiatric diagnosis, full-scale IQ and COMT Val158Met genotype were determined in the 22q11DS group. Substance use data were collected according to the Composite International Diagnostic Interview.ResultsThe prevalence of total substance use (36.9%) and substance use disorders (1.2%), and weekly amounts of alcohol and nicotine use, in patients with 22q11DS was significantly lower than in non-deleted patients with psychosis or controls. Compared with patients with 22q11DS, healthy controls were 20 times more likely to use substances in general (P < 0.001); results were also significant for alcohol and nicotine use separately. Within the 22q11DS group, there was no relationship between the prevalence of substance use and psychosis or COMT genotype. Male patients with 22q11DS were more likely to use substances than female patients with 22q11DS.ConclusionsThe results suggest that patients with 22q11DS are at decreased risk for substance use and substance use disorders despite the increased risk of psychotic disorders. Further research into neurobiological and environmental factors involved in substance use in 22q11DS is necessary to elucidate the mechanisms involved.Declaration of interestNone.

This report describes a newborn girl presenting with some of the common features of DiGeorge syndrome/velocardiofacial syndrome (DGS/VCFS), including hypocalcemia, atrial septal defect, and aortic stenosis. Several genetic tests were carried out to determine the origin of the clinical phenotype. MLPA was initially performed followed by aCGH, cytogenetic analysis, and FISH. Cytogenetic analysis of the proband's parents was also done. MLPA revealed a deletion in 22q11.1q11.2 spanning from the cat eye syndrome region to the most commonly deleted region in DGS/VCFS patients. The size of the deletion as defined by aCGH was 3.2 Mb. The karyotype of the proband was 45,XX,der(1)t(1;22)(p36.3;q11.2)dn,-22, the karyotypes of the parents were normal. FISH analysis showed that the 22q11 deletion occurred in the der(1). No loss or gain of chromosomal material was evident for chromosome 1, as confirmed by MLPA, aCGH, and FISH. Unbalanced translocations resulting in DGS are relatively rare, with limited reports in the literature. To our knowledge, this is the second case involving chromosome 1 and the first one with breakpoints in 1p36 and 22q11.2. This case also emphasizes the importance of combining diagnostic methods to better understand a given genetic abnormality.

Aim 22q11 microdeletion syndrome has an increased risk for psychosis, similar to subjects at ultra-high risk for psychosis. Neurological soft signs are considered an endophenotype of psychotic disorders and a marker of vulnerability to Schizophrenia, consisting of overflow movements, dysrhythmia and speed of timed activities. To date, there are no studies that have evaluated the presence of the neurological soft signs in subjects with 22q11 microdeletion syndrome and there are a few studies that have analysed this issue in subjects at ultra-high risk. Methods We sought to measure neurological soft signs in these two conditions, compared to healthy controls and to analyse the possible correlation between neurological soft signs and positive/negative symptoms both in 22q11 microdeletion syndrome and ultra-high-risk groups. 54 drug-naive patients (29 with 22q11 microdeletion syndrome and 25 at ultra-high risk for psychosis) and 25 healthy controls were evaluated for neurological soft signs. Results Both clinical groups showed a greater number of neurological soft signs compared to healthy control, although the two clinical groups did not differ for the number of neurological soft signs. Positive correlation between speed of timed activities and negative symptoms was found in subjects at ultra-high risk. Conclusion Neurological soft signs could represent a marker of atypical neurodevelopment in the two populations examined. Since we did not found a strong correlation between neurological soft signs and positive/negative symptoms, we suggest that neurological soft signs could be indicators of vulnerability to psychosis independent from the psychopathology.

Background 22q11.2 deletion syndrome (22q11.2DS) is a multisystem condition associated with an increased risk of early-onset Parkinson's disease (PD). Methods We review the clinical, neuroimaging, and neuropathological observations, as well as diagnostic challenges, of PD in 22q11.2DS. We conducted a search of PubMed up until June 1, 2018 and personal files to identify relevant publications. Results 22q11.2DS-associated PD is responsible for approximately 0.5% of early-onset PD. The hallmark motor symptoms and neuropathology of PD, and typical findings of reduced striatal dopamine transporter binding with molecular imaging, are present in 22q11.2DS-associated PD. Mean age at PD onset in 22q11.2DS is relatively young (∼40 years). Patients with 22q11.2DS-associated PD show a good response to levodopa. Conclusions Further recognition of 22q11.2DS and study of PD in people with 22q11.2DS could provide insights into the mechanisms that cause PD in the general population. 22q11.2DS may serve as an identifiable PD model to study prodromal PD and disease-modifying treatments.

Objective: Discuss a unique presentation of hypoparathyroidism, an orphan disease with an estimated prevalence of 37 per 100,000 person-years in the United States.Methods: Describe the clinical presentation and pertinent laboratory data of a case of newly diagnosed hypoparathyroidism presenting as acute cardiomyopathy. A related literature review is also included.Results: A 34-year-old, previously healthy Caucasian female presented to the emergency room with progressive symptoms of heart failure and was found to have anemia, hypocalcemia, and hypoparathyroidism with an ejection fraction (EF) of 25 to 30% without structural cardiac abnormalities. Her labs revealed her hemoglobin was 6.4 g/dL, calcium was 4.9 mg/dL (reference range is 8.5 to 10.2 mg/dL), albumin was 3.4 g/dL (reference range is 3.5 to 5.5 g/dL), magnesium was 1.3 mg/dL (reference range is 1.7 to 2.2 mg/dL), phosphate was 4.9 mg/dL (reference range is 2.5 to 4.5 mg/dL), parathyroid hormone was 9 pg/mL (reference range is 14 to 64 pg/mL), and 25-hydroxyvitamin D was 31.9 ng/mL (reference range is 30 to 79 ng/mL). Pertinent history included normal early development, no previous neck surgery or radiation, and no family history of hypocalcemia, seizures, or intellectual disability. The patient did note recurrent ear infections. On physical exam, the patient had a nasal voice but no dysmorphic facies or visible palatal abnormalities and a normal cardiac exam. The patient's EF improved to 35% by hospital day 8 with stabilization of calcium levels. In follow-up, her EF was 50 to 55% at 1 month and then 60% at 5 months. Genetic testing revealed 22q11.2 deletion.Conclusion: This is the first reported adult case of 22q11 deletion syndrome presenting with reversible heart failure due to hypocalcemia secondary to hypoparathyroidism. Genetic testing is recommended for all cases of hypoparathyroidism without a clear known etiology even if they present in adulthood.Abbreviations: 22q11DS = 22q11 deletion syndrome; EF = ejection fraction

Contains fulltext : 237899.pdf (Publisher’s version ) (Closed access) The Koolen-de Vries syndrome (KdVS) is a multisystem syndrome with variable facial features caused by a 17q21.31 microdeletion or KANSL1 truncating variant. As the facial gestalt of KdVS has resemblance with the gestalt of the 22q11.2 deletion syndrome (22q11.2DS), we assessed whether our previously described hybrid quantitative facial phenotyping algorithm could distinguish between these two syndromes, and whether there is a facial difference between the molecular KdVS subtypes. We applied our algorithm to 2D photographs of 97 patients with KdVS (78 microdeletions, 19 truncating variants (likely) causing KdVS) and 48 patients with 22q11.2DS as well as age, gender and ethnicity matched controls with intellectual disability (n = 145). The facial gestalts of KdVS and 22q11.2DS were both recognisable through significant clustering by the hybrid model, yet different from one another (p = 7.5 × 10(-10) and p = 0.0052, respectively). Furthermore, the facial gestalts of KdVS caused by a 17q21.31 microdeletion and KANSL1 truncating variant (likely) causing KdVS were indistinguishable (p = 0.981 and p = 0.130). Further application to three patients with a variant of unknown significance in KANSL1 showed that these faces do not match KdVS. Our data highlight quantitative facial phenotyping not only as a powerful tool to distinguish syndromes with overlapping facial dysmorphisms but also to establish pathogenicity of variants of unknown clinical significance.

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.

Aims 22q11 Deletion Syndrome (22q11DS) or DiGeorge syndrome is commonly first considered and diagnosed at cardiac centres due to its association with several forms of congenital heart disease. Due its multi-system involvement, it is important to screen children with 22q11DS for common problems early and refer promptly. The aims of this project were to: 1. Audit our practice against any national standards of initial investigations. 2. Create a local pathway and checklist for initial management of suspected or confirmed DiGeorge syndrome. Methods We used the MaxAppeal (www.maxappeal.org.uk) consensus document on 22q11DS to formulate a list of standards to retrospectively audit against. We then used our local electronic patient record system to search for all children who had been admitted under cardiology with a diagnosis of 22q11DS syndrome between 2014–2018. We searched our laboratory, radiology and other electronic patient record system to record if and when they had certain investigations. We excluded patients whose care was primarily under another hospital. Results We found 46 patients diagnosed between 2014–2018 but 21 of these had their care under another hospital. 23 out of the remaining 25 had a period of inpatient care and 17 of the 25 were diagnosed with 22q11DS during their first admission to hospital. 4/25 were diagnosed antenatally. We performed well on ensuring all our children had a baseline full blood count with white cell differentials and plasma calcium. However, only 7/25 had a thyroid function test. Unsurprisingly all 25 patients had a full cardiac examination and ECHO. Renal ultrasound was performed in 17/25 of our patients. The largest room for improvement was in baseline immunology investigations; only 7/25 had lymphocyte phenotyping and 6/25 had immunoglobulins tested. Conclusion The data shows that 22q11DS is a not uncommon clinical diagnosis in the tertiary cardiac centre. There are multiple considerations in management and investigations and our retrospective audit shows that there is room for improvement, particularly in immunological investigation. We are developing a proforma for suspected and confirmed 22q11DS and will be presenting this locally for approval and dissemination.

To prospectively quantify bleeding severity and elaborate hemorrhagic symptoms in children with 22q11.2 deletion syndrome (22q11DS) using 2 validated bleeding assessment tools (BATs), namely the Pediatric Bleeding Questionnaire and the International Society on Thrombosis and Hemostasis BAT (ISTH-BAT). We also sought to compare subjects' bleeding scores to unaffected first-degree family members.Children with 22q11DS and unaffected first-degree family members were recruited for the study. Two validated BATs were administered by a pediatric hematologist. Additional clinical and laboratory data were abstracted from patient medical records. Standard descriptive and nonparametric statistical methods were used.In total, 29 eligible subjects and controls were assessed. Median age (range) of subjects and controls was 8 (5-17) years and 38 (9-56) years, respectively. In total, 17 of 29 subjects had a positive bleeding score on ISTH-BAT compared with 1 of 29 control patients (P .0001). Median ISTH-BAT score in subjects was 3 (0-12), compared with 2 (0-6) in control patients (P = .022). Median Pediatric Bleeding Questionnaire score in subjects was 2 (-1 to 12). The most frequent bleeding symptoms reported in subjects with 22q11DS were epistaxis (69%) and bruising (52%). Eighteen subjects had been surgically challenged, and 6 were noted to have increased perioperative hemorrhage.Children with 22q11DS have increased bleeding scores compared with their first-degree unaffected relatives. The majority of the bleeding symptoms described were mucocutaneous.

22q11 deletion syndrome (22q11DS), also known as DiGeorge syndrome or velocardiofacial syndrome, is the most common human genetic microdeletion. Hypocalcemia secondary to hypoparathyroidism is a common finding in this condition and may present with seizures. We describe a case of an 11-day-old male presenting with hypocalcemic seizures and a positive newborn screen for severe combined immunodeficiency as the primary manifestations of 22q11DS. Given the potential for wide phenotypic variability, clinicians should maintain a high index of suspicion for this syndrome, especially in the neonate presenting with hypocalcemia.

Background To delineate sleep habits and problems in children with 22q11.2 deletion syndrome (22q11DS). Methods Thirty children, age 1–15 (mean 6.8) years, participated in the study, which was an internet‐based anonymous survey of parents of children with 22q11DS administered via the 22q11.2 Foundation. The main outcome was the Childhood Sleep Habits Questionnaire (CSHQ). Results Scores on the CSHQ demonstrated clinically significant sleep problems in 29 of the 30 children. When compared with previously reported normative values for typically developing children of the same age, children with 22q11DS had significantly greater sleep problems. Only 30% of children had previously undergone sleep study. While about half of children had tried a medication for sleep, it usually was not felt to be helpful. In contrast, parents reported that behavioral interventions, such as consistent bedtime routine and appropriate sleep environment, were helpful. This is one of the first studies to specifically address sleep problems other than obstructive sleep apnea in children with 22q11DS. Conclusions The findings suggest children with 22q11DS may have a higher risk of experiencing clinical sleep problems, compared to typically developing children. Consideration of additional screening and treatment of sleep disorders in children with 22q11DS is warranted., Scores from the Childhood Sleep Habits Questionnaire, a validated survey tool, suggest children may have a higher risk of experiencing clinical sleep problems if diagnosed with 22q11DS compared to typically developing children. Consideration of additional screening and treatment of sleep disorders in children with 22q11DS is warranted.

Tympanostomy tube otorrhea (TTO) is a common complication of tympanostomy tubes. The most common bacteria associated with TTO include Haemophalis influenza, Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. We present the first case of a 9 year-old female with a history of 22q11 syndrome, hemifacial microsomia, Tetralogy of Fallot, and hearing aid dependence with left-sided profound sensorineural and right-sided moderate conductive hearing loss who presented with TTO caused by the bacteria Pigmentiphaga daeguenesis/kulla, a gram-negative bacteria often found in soil. This patient's otorrhea did not respond to typical otic antibiotic formulations, but was ultimately treated successfully with intramuscular ceftriaxone. We describe the natural history, presentation and management for a case of TTO caused by a rare bacteria from the genus Pigmentiphaga.

22q11.2 deletion syndrome (22q11.2DS) is considered one of the most frequently observed chromosomal abnormalities in association with congenital heart disease (CHD), which can also include some combination of other features. Thus, the aim of this work was to verify the profile of dysmorphic features and heart defects found in patients referred to a reference center in Southern Brazil with clinical findings suggestive of 22q11.2DS. In the overall sample group, only patients with dysmorphic facial features (skull, eyes, ear, and nose) associated with CHD (obstructive pulmonary valve ring, truncus arteriosus, and bicuspid aortic valve associated with atrial septal defect and/or right aortic arch) had a 22q11.2 deletion. These findings proved to be reliable clinical criteria for referral to perform fluorescent in situ hybridization investigation for 22q11.2 deletion.

Disrupted development of oropharyngeal structures as well as cranial nerve and brainstem circuits may lead to feeding and swallowing difficulties in children with 22q11. 2 deletion syndrome (22q11DS). We previously demonstrated aspiration-based dysphagia during early postnatal life in the LgDel mouse model of 22q11DS along with disrupted oropharyngeal morphogenesis and divergent differentiation and function of cranial motor and sensory nerves. We now ask whether feeding and swallowing deficits persist in adult LgDel mice using methods analogous to those used in human patients to evaluate feeding and swallowing dysfunction. Compared to wild-type mice, videofluoroscopic swallow study revealed that LgDel mice have altered feeding and swallowing behaviors, including slower lick rates, longer inter-lick intervals, and longer pharyngeal transit times with liquid consistency. Transoral endoscopic assessment identified minor structural anomalies of the palate and larynx in one-third of the LgDel mice examined. Video surveillance of feeding-related behaviors showed that LgDel mice eat and drink more frequently. Furthermore, LgDel animals engage in another oromotor behavior, grooming, more frequently, implying that divergent craniofacial and cranial nerve structure and function result in altered oromotor coordination. Finally, LgDel mice have significantly increased lung inflammation, a potential sign of aspiration-based dysphagia, consistent with results from our previous studies of early postnatal animals showing aspiration-related lung inflammation. Thus, oromotor dysfunction, feeding, and swallowing difficulties and their consequences persist in the LgDel 22q11DS mouse model. Apparently, postnatal growth and/or neural plasticity does not fully resolve deficits due to anomalous hindbrain, craniofacial, and cranial nerve development that prefigure perinatal dysphagia in 22q11DS. This new recognition of persistent challenges with feeding and swallowing may provide opportunities for improved therapeutic intervention for adolescents and adults with 22q11DS, as well as others with a history of perinatal feeding and swallowing disorders. Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health [5P01HD083157]; Intellectual and Developmental Disabilities Research Center Award through the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health [U54HD090257] The behavioral and craniofacial analysis for this work were supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (5P01HD083157). The microscopic analysis for this study was conducted at the CRI Light Microscopy and Image Analysis Core, supported by the Intellectual and Developmental Disabilities Research Center Award (U54HD090257) through the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.

Background The 22q11.2 deletion syndrome (22q11.2DS) is the most common contiguous microdeletion affecting humans and exhibits extreme phenotypic heterogeneity. Patients can manifest any combination of comorbidities including congenital heart disease, hypoparathyroidism, cleft palate, kidney abnormalities, neurodevelopmental disorders, and immune dysfunction. Immunodeficiency is present in the majority of patients with 22q11.2DS and is the second leading cause of death in these patients. Knowing the genetic determinants of immune dysfunction will aid in prognostication and potentially novel treatments. Methods We performed exome sequencing and gene‐based variant association analysis on 31 deeply phenotyped individuals with the canonical 3Mb 22q11.2 deletion to identify what genes outside the 22q11.2 locus may be modifying the immune dysregulated phenotype. Immunophenotyping was performed using preexisting medical data and a novel scoring system developed from numerous clinical laboratory values including immunoglobulin levels, lymphocyte transformation to antigens (LTA), lymphocyte transformation to mitogens (LTM), and peripheral blood flow cytometry. Immunophenotypic scoring was validated against newborn screening T‐cell receptor excision circle (TREC) results. Results Rare DNA variants in transcriptional regulators involved in retinoic acid signaling (NCOR2, OMIM *600848 and EP300, OMIM *602700) were found to be associated with immunophenotype. Conclusion The expression of TBX1, which seems to confer the major phenotypic features of 22q11.2DS, is regulated via retinoic acid signaling, and alterations in retinoic acid signaling during embryonic development can lead to phenocopies of 22q11.2DS. These observations support the hypothesis that genetic modifiers outside the microdeletion locus may influence the immune function in 22q11.2DS patients., We performed deep phenotyping for immune status on 31 individuals with the canonical 3Mb 22q11.2 deletion followed by whole exome sequencing. DNA variants in transcriptional regulators involved in retinoic acid signaling (NCOR2, EP300) were found to be associated with immune status.

Individuals with 22q11.2 deletion syndrome (22q11DS) show high rates of anxiety associated with their increased risk of developing schizophrenia. Biased attention is associated with anxiety and is important to investigate in those with 22q11DS given this association. We analyzed attention bias to emotional faces in 7- to 17-year olds with 22q11DS and typically developing controls (TD) using a dot probe threat bias paradigm. We measured response time, eye tracking, and pupilometry. Those with 22q11DS showed no significant changes in early versus late trials, whereas those who were TD showed differing patterns in both gaze and pupilometry over time. The patterns in those who are TD may indicate adaptation that is lacking or slower in individuals with 22q11DS.

The neural crest is an important transient structure that develops during embryogenesis in vertebrates. Neural crest cells are multipotent progenitor cells that migrate and develop into a diverse range of cells and tissues throughout the body. Although neural crest cells originate from the ectoderm, they can differentiate into mesodermal-type or endodermal-type cells and tissues. Some of these tissues include the peripheral, autonomic, and enteric nervous systems; chromaffin cells of the adrenal medulla; smooth muscles of the intracranial blood vessels; melanocytes of the skin; cartilage and bones of the face; and parafollicular cells of the thyroid gland. Neurocristopathies are a group of diseases caused by the abnormal generation, migration, or differentiation of neural crest cells. They often involve multiple organ systems in a single person, are often familial, and can be associated with the development of neoplasms. As understanding of the neural crest has advanced, many seemingly disparate diseases, such Treacher Collins syndrome, 22q11.2 deletion syndrome, Hirschsprung disease, neuroblastoma, neurocutaneous melanocytosis, and neurofibromatosis, have come to be recognized as neurocristopathies. Neurocristopathies can be divided into three main categories: dysgenetic malformations, neoplasms, and combined dysgenetic and neoplastic syndromes. In this article, neural crest development, as well as several associated dysgenetic, neoplastic, and combined neurocristopathies, are reviewed. Neurocristopathies often have clinical manifestations in multiple organ systems, and radiologists are positioned to have significant roles in the initial diagnosis of these disorders, evaluation of subclinical associated lesions, creation of treatment plans, and patient follow-up. Online supplemental material is available for this article. ©RSNA, 2019.

22q deletion syndrome (22q11.2DS) is most often correlated prenatally with congenital heart disease and or cleft palate. The extracardiac fetal phenotype associated with 22q11.2DS is not well described. We sought to review both the fetal cardiac and extracardiac findings associated with a cohort of cases ascertained prenatally, confirmed or suspected to have 22q11.2DS, born and cared for in one center. A retrospective chart review was performed on a total of 42 cases with confirmed 22q11.2DS to obtain prenatal findings, perinatal outcomes and diagnostic confirmation. The diagnosis was confirmed prenatally in 67% (28/42) and postnatally in 33% (14/42). The majority (81%) were associated with the standard LCR22A-LCR22D deletion. 95% (40/42) of fetuses were prenatally diagnosed with congenital heart disease. Extracardiac findings were noted in 90% (38/42) of cases. Additional findings involved the central nervous system (38%), gastrointestinal (14%), genitourinary (16.6%), pulmonary (7%), skeletal (19%), facial dysmorphism (21%), small/hypoplastic thymus (26%), and polyhydramnios (30%). One patient was diagnosed prenatally with a bilateral cleft lip and cleft palate. No fetus was diagnosed with intrauterine growth restriction. The average gestational age at delivery was 38 weeks and average birth weight was 3,105 grams. Sixty-two percentage were delivered vaginally and there were no fetal demises. A diagnosis of 22q11.2 deletion syndrome should be considered in all cases of prenatally diagnosed congenital heart disease, particularly when it is not isolated. Microarray is warranted in all cases of structural abnormalities diagnosed prenatally. Prenatal diagnosis of 22q11.2 syndrome can be used to counsel expectant parents regarding pregnancy outcome and guide neonatal management.

Craniofacial Microsomia (CFM) also known as Oculo-auriculo-vertebral Spectrum (OAVS) or Goldenhar Syndrome, presents wide phenotypic and etiological heterogeneity. It affects mainly the structures originated from the first and second pharyngeal arches. In addition, other major anomalies may also be found, including congenital heart diseases. In this study, we report a patient with distal deletion in the 22q11.2 region and a phenotype which resembles CFM. The proband is a girl, who presented bilateral preauricular tags, left auditory canal stenosis, malar hypoplasia, cleft lip and palate, mild asymmetry of soft tissue in face, congenital heart disease, intestinal atresia, annular pancreas and hydronephrosis. The genomic imbalances investigation by Multiplex Ligation-dependent Probe Amplification (MLPA) and Chromosomal Microarray Analysis (CMA) revealed a distal deletion of 1,048 kb at 22q11.2 encompassing the region from Low Copy Repeats (LCRs) D to E. We did review of the literature and genotype-phenotype correlation. This is the sixth case of distal 22q11.2 deletion resembling CFM and the second encompassing the region between LCRs D to E. All cases share some phenotypic signs, such as preauricular tags, facial asymmetry, cleft lip and palate, and congenital heart diseases. Candidate genes in this region have been studied by having an important role in pharyngeal arches developmental and in congenital heart diseases, such as HIC2, YPEL1and MAPK1/ERK2. This case corroborates the phenotypic similarity between 22q11.2 distal deletion and CFM/OAVS. It also contributes to genotype-phenotype correlation and reinforces that candidate genes for CFM, in the 22q11.2 region, might be located between LCRs D and E.

Summary DiGeorge syndrome or 22q11.2 deletion syndrome is one of the most common genetic microdeletion syndromes in humans. In addition to physical manifestations, DiGeorge syndrome is associated with a high prevalence of psychiatric disorders, such as intellectual disability, schizophrenia and attention-deficit/hyperactivity disorder. Usually, the diagnosis of DiGeorge syndrome is made in early childhood. This article reports on the late diagnosis of a patient with panic disorder and comorbid major depression at the age of 51. Since genetic testing was not available before the 1990s, there might be many over 40-year-old patients, who remained undiagnosed. Psychiatric symptoms exhibit distinctive developmental trajectories and many of these exhibit an increase in incidence during adulthood. Hence, undiagnosed adult DiGeorge patients might present in psychiatric services. As in this case, a correct diagnosis of DiGeorge syndrome in adults may help to improve treatment and outcome.

Objective: Identify an endocrine developmental syndrome (DiGeorge syndrome, or 22q11 deletion syndrome) that had been previously undiagnosed in an adult patient.Methods: The patient was evaluated in an adult endocrinology clinic. In particular, fluorescence in situ hybridization was used to identify a segmental deletion on chromosome 22.Results: DiGeorge syndrome was positively identified using fluorescence in situ hybridization in our patient.Conclusion: Rare developmental syndromes may be initially diagnosed in adult patients. DiGeorge syndrome should be among the differential diagnoses considered in an adult with hypocalcemia.Abbreviations: 22q11DS 22q11 deletion syndrome DGCR DiGeorge critical region FISH fluorescence in situ hybridization PTH parathyroid hormone

Background 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a variety of negative health, cognitive, emotional, and behavioral outcomes. 22q11DS is comorbid with many psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The current study aimed to investigate the cognitive, behavioral, and functional outcomes that a childhood ADHD diagnosis predicts to in adulthood. Methods This longitudinal study followed 52 individuals with 22q11DS over 9 years. Childhood ADHD was operationalized both categorically (Diagnostic and statistical manual - 4th edition (DSM-IV) ADHD diagnoses) and dimensionally (inattentive and hyperactive-impulsive symptoms) and was tested as predictors of young adult outcomes. Results As young adults, children with 22q11DS + baseline ADHD had more parent-reported executive dysfunction and lower levels of clinician-rated overall functioning than those with 22q11DS yet without ADHD. Dimensional symptoms of ADHD in childhood did not predict young adult outcomes. No self-report differences emerged between those with and without baseline ADHD. The majority (82.4%) of individuals with 22q11DS + baseline ADHD were never treated with an ADHD medication. Conclusions A categorical diagnosis of ADHD in childhood predicted a greater variety of worse outcomes than dimensional levels of ADHD symptoms. Despite the significant impact of comorbid ADHD in 22q11DS, evidence-based treatment rates were low.

Background Individuals with 22q11.2 deletion syndrome (22q11DS) have a 25% risk for schizophrenia and related psychotic disorders. Some have hypothesized that Autism Spectrum Disorders (ASDs) diagnosed in children with 22q11DS may actually represent the social-communicative defects often observed during the early developmental stages of schizophrenia. Methods We prospectively studied 89 children with 22q11DS to test this hypothesis. At baseline, the Autism Diagnostic Interview was used to assess ASD, evaluating both current and early childhood behaviors. At follow-up, the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) was used to determine development of a psychotic disorder or psychotic symptoms. Results The average age (± SD) at first and last assessments was 14.3 ± 1.9 and 19.0 ± 3.0 years, respectively. Nineteen (21.3%) children developed a psychotic disorder. Contrary to our hypothesis, there was no significant difference in the proportion that developed a psychotic disorder, comparing those with (n = 9, 17.3%) and those without ASD at baseline (n = 10, 27%; OR = 0.500, 95% CI = 0.160–1.569, p = 0.235). Similar results were obtained using autistic symptom severity as quantitative predicting variable, psychotic symptoms as the outcome, and when correcting for age, gender and full scale IQ. Conclusion Results indicate that in children with 22q11DS, early childhood autistic features are not associated with an increased risk for subsequent development of psychotic disorders or symptoms, replicating previous retrospective findings in adults with 22q11DS. These results indicate that ASD and psychotic disorders can emerge independently, as pleiotropic phenotypes in the context of 22q11DS.

Background 22q11 deletion syndrome (also known as DiGeorge syndrome and velocardiofacial syndrome) is the most common microdeletion syndrome. The condition typically presents with one or more of congenital heart disease, palatal and ear nose and throat abnormalities, hypocalcaemia and hypoparathyroidism, immune deficiency and developmental delay. Given the wide variety of medical and surgical manifestations of this syndrome, diagnosis and follow-up if often a clinical challenge. Objective The aim of this study was to review current literature and guidelines on 22q11 deletion syndrome to develop a clinical tool summarizing avaible evidence. This is to aid in recognition, investigation and appropriate follow-up from the neonatal period. Method A systematic literature search was conducted to gather all available evidence pertinent to the diagnosis long-term care of neonates and children with suspected or confirmed 22q11 deletion syndrome. Furthermore, current published guidelines, consensus statements and expert opinion was included. Results The initial search returned 446 results, of which 57 articles were included in the final analysis. The literature reflected the wide phenotypic variation seen 22q11 deletion syndrome. The most common presentations were cardiac malformations, developmental delay, palatal abnormalities, immunodeficiency and hypocalcemia. Follow-up is very much dependent on the specific manifestations, with limited evidence supporting any universal best practice approach. Based on the review conducted by this group, a clinical tool (in the form of a single-page flow-chart) was developed to outline the key areas in the long-term care of patients with 22q11 deletion syndrome. Conclusion A multidisciplinary approach to this complex syndrome is essential as the age and features at the time of diagnosis are variable. Neonatal diagnosis is becoming more common, and comprehensive checklists with evidence-based recommendations are valuable in clinical practice. A clinical tool was designed by this group with the intent of guiding decision making, integrating the many aspects of care in this population, and ultimately promote better long-term outcomes for patients.

Background Chromosome 22q11.2 deletion syndrome (22q11DS) is a promising model for studying psychosis risk. Direct comparisons of psychosis features between 22q11DS and nondeleted (ND) individuals are limited by inconsistency and small samples. In the largest study to date, we compare 22q11DS to ND in comorbidities, functioning, cognition, and psychosis features across the full range of overall severity. Methods ND youths ( n = 150) ages 9 to 24 years were matched to 22q11DS individuals ( n = 150) on age and sex, stratifying for presence of psychosis-spectrum disorder. Individuals were evaluated for psychosis using the Structured Interview for Prodromal Syndromes, and for attention-deficit/hyperactivity, substance-related, and mood disorders. Differential item functioning analysis addressed whether 22q11DS differs from ND in the probability of clinically significant ratings while holding constant the overall level of psychosis. Results Onset of psychosis proneness was similar among 22q11DS (mean: 11.0 years) and ND (mean: 12.1 years) individuals. Accounting for higher overall psychosis symptoms, 22q11DS participants were still more likely to manifest impaired stress tolerance, avolition, and ideational richness; ND individuals were more likely to exhibit unusual thoughts, persecutory ideas, and bizarre thinking. Cognition was impaired in 22q11DS, but it did not correlate with symptoms except ideational richness. Comorbid anxiety disorders were more likely in psychosis-spectrum 22q11DS; substance-related disorders were more likely in ND. Global assessment of function was similar in 22q11DS and ND individuals, except among those with low total Structured Interview for Prodromal Syndromes scores. Conclusions Individuals with 22q11DS share overarching similarities with ND individuals in psychosis symptoms and age of onset for psychosis proneness; this continues to support the 22q11DS model as a valuable window into mechanisms contributing to psychosis.

Neonatal hypocalcemia and congenital heart defects has been known as the first clinical manifestation of the chromosome 22q11.2 deletion syndrome (22q11DS). However, because of its wide clinical spectrum, diagnosis of 22q11DS can be delayed in children without classic symptoms. We report the case of a girl with the history of imperforate anus but without neonatal hypocalcemia or major cardiac anomaly, who was diagnosed for 22q11DS at the age of 11 after the onset of overt hypocalcemia. She was born uneventfully from phenotypically normal Korean parents. Imperforate anus and partial cleft palate were found at birth, which were surgically repaired thereafter. There was no history of neonatal hypocalcemia, and karyotyping by GTG banding was normal. At the age of 11, hypocalcemia (serum calcium, 5.0 mg/dL) and decreased parathyroid hormone level (10.8 pg/mL) was noted when she visited our Emergency Department for fever and vomiting. The 22q11DS was suspected because of her mild mental retardation and velopharyngeal insufficiency, and a microdeletion on chromosome 22q11.2 was confirmed by fluorescence in situ hybridization. The 22q11DS should be considered in the differential diagnosis of hypocalcemia at any age because of its wide clinical spectrum.

Ventral and dorsal streams are visual pathways deputed to transmit information from the photoreceptors of the retina to the lateral geniculate nucleus and then to the primary visual cortex (V1). Several studies investigated whether one pathway is more vulnerable than the other during development, and whether these streams develop at different rates. The results are still discordant. The aim of the present study was to understand the functionality of the dorsal and the ventral streams in two populations affected by different genetic disorders, Noonan syndrome (NS) and 22q11.2 deletion syndrome (22q11.2DS), and explore the possible genotype-phenotype relationships. 'Form coherence' abilities for the ventral stream and 'motion coherence' abilities for the dorsal stream were evaluated in 19 participants with NS and 20 participants with 22q11.2DS. Collected data were compared with 55 age-matched controls. Participants with NS and 22q11.2DS did not differ in the form coherence task, and their performance was significantly lower than that of controls. However, in the motion coherence task, the group with NS and controls did not differ, and both obtained significantly higher scores than the group with 22q11.2DS. Our findings indicate that deficits in the dorsal stream are related to the specific genotype, and that in our syndromic groups the ventral stream is more vulnerable than the dorsal stream.

Objectives This article reports the safety and efficacy of a morphology-based algorithm for the surgical management of pulmonary atresia and ventricular septal defect with major aortopulmonary collateral arteries. Methods A total of 83 patients were operated from 2007 to 2014 using 3 surgical approaches: one-stage total repair, one-stage unifocalization with central shunt and delayed total repair and multistage unifocalization with subsequent total repair. Patients were divided into 2 groups depending on the surgical strategy used to choose the surgical approach. In Group I (2007-09), the surgeon-preferred procedure (71%-one-stage total repair) was used. In Group II (2010-14), a surgical algorithm based on pulmonary arterial tree morphology was applied. Results Median follow-up was 5.04 years and 98% complete. The overall survival rate was 92.59%. Cumulative operative mortality decreased from 10.7% in Group I to 0% in Group II ( P = 0.036). Successful complete repair was performed in 23 (82%) of 28 patients in Group I (median follow-up, 7.99 years) and in 33 (60%) of 55 patients in Group II (median follow-up, 3.85 years). The difference in total survival was not significant between Groups I and II but was markedly influenced by the presence of the 22q11 deletion. The survival of 23 patients with confirmed 22q11 deletion was 73.91%; the survival of 28 patients with confirmed absence of the 22q11 deletion was 100%; and the survival of 32 patients not tested for the 22q11 deletion was 100% ( P = 0.0001). Conclusions Total survival was significantly lower in patients with the 22q11 deletion. Surgical management based on preoperative pulmonary arterial anatomical features improves early surgical results.

22q11.2 deletion syndrome (22q11.2DS) has a wide range of clinical features including endocrine abnormalities. We aimed to characterize growth patterns, hypoparathyroidism, and thyroid dysfunction of individuals with 22q11.2DS. Anthropometric and laboratory measurements were obtained from the charts of 48 individuals (males=28, 8.0±6.8 visits/participant) followed at a national 22q11.2DS clinic between 2009 and 2016. Age at diagnosis was 4.3±4.9 years and age at last evaluation 11.2±7.2 years. Median height-SDS was negative at all ages. Height-SDS at last visit was correlated to the midparental height-SDS (r=0.52 P=0.002). Yet, participants did not reach their target height, with a difference of 1.06±1.07 SD (P

Di-George syndrome (DGS) is amongst the commonest genetic disorders caused by microdeletions in the long arm of chromosome 22, resulting in a phenotypically similar syndrome. It ultimately affects many organs and systems leading mainly to cardiac malformations, hypocalcaemia and thymic impairment. Dysfunction of the thymus was associated with immune dysfunction. The association between DGS and autoimmune diseases like primary biliary cirrhosis (PBC) and rheumatoid arthritis (RA) is under investigation. PBC is an autoimmune disease affecting the intrahepatic ducts leading to progressive cholestasis and end-stage liver disease. RA is an autoimmune chronic inflammatory disease of multiple joints. PBC and RA rarely co-exist (frequency 1.8–5.6%). Genetic, epigenetic and environmental factors play a role. In this case report, we describe the unique case of a 22-year female with a partial DGS who was initially diagnosed with PBC and a year after with RA. It is early to answer the possible reasons of the ...

OBJECTIVE The focus of this study was to evaluate the prevalence, type, and severity of hearing impairment in patients with velo-cardio-facial syndrome (VCFS) and to compare these characteristics with patient demographics and other otologic factors. STUDY DESIGN Retrospective analysis of the AudGen Database. SETTING Tertiary academic referral center. PATIENTS Pediatric patients in AudGenDB with a diagnosis of velo-cardio-facial syndrome or DiGeorge syndrome. INTERVENTIONS Appropriate audiologic, otologic, and demographic data were recorded. MAIN OUTCOME MEASURE Four hundred six patients met inclusion criteria. Data for each patient were selected based on their encounters with earliest complete audiometric data, and hearing loss (HL) was defined as greater than 15 dB HL at any threshold by pure tone or greater than 20 dB HL by soundfield audiometry. The patients were then stratified by type and severity of HL, and available otologic and medical conditions were documented. RESULTS Two hundred forty eight (60.7%) patients had HL. Of the 391 individual HL ears, 127 had conductive, 22 had sensorineural, 115 had mixed, and 127 had unspecified hearing loss. 57% of the loss was bilateral. Patients with mixed HL had significantly worse pure-tone averages (PTAs). CONCLUSION HL is prevalent in patients with VCFS. The hearing loss is primarily of conductive origin, with a predisposition to be bilateral, with mixed HL typically have more severe loss. There were a large number of patients with sensorineural hearing loss components as well. Further studies are needed to investigate the causal nature of the hearing impairment in VCFS, to better aid otolaryngologist and audiologists when assessing these patients.

International audience; In this study, we describe the biological immune profiles and clinical dysimmune manifestations (infections, autoimmune diseases, and allergies) of patients with 22q11.2 deletion syndrome with the aim of determining risk factors for clinical events. This retrospective study concerned all the patients with 22q11 deletion syndrome attending the Montpellier University Hospital from January 1, 1992, to December 31, 2014 who had at least one immune investigation before the age of 18. We analyzed the clinical features, biological tests and the course of infections, autoimmunity, and allergy of 86 children. Among these 86 children, 48 (59%) had a low T lymphocyte level. Twenty-nine patients (34%) had a severe infection. The only risk factor for severe infection was the low level of CD4+ T-cells (OR: 3.3; 95% confidence interval (CI) [1.020-11.108]). Eleven patients (13%) developed an autoimmune disease; the only risk factor was an antecedent of severe infection (OR: 4.1; 95% CI [1.099-15.573]). Twenty-three patients (27%) had allergic episodes. A low level of CD8+ T-cells (OR: 3.2; 95% CI [1.07-9.409]) was significantly associated with allergy manifestations. Patients with 22q11 deletion syndrome have a high rate of dysimmune manifestations. We found statistic correlations among CD4+ T-cell count, infectious manifestations, and autoimmunity.