Search

22q11.2 deletion syndrome (22.q11.2 DS) is a genetic syndrome resulting from a microdeletion on chromosome 22. It has a diverse array of manifestations, and most cases are diagnosed early in childhood. We present the case of a 38-year-old female born in a developing country who presented to our clinic to establish care for a history of primary hypothyroidism. She was clinically and biochemically euthyroid on thyroid supplementation. She was also noted to have hypocalcemia in the setting of low PTH, for which the patient was previously prescribed calcitriol. Given a history of cleft palate, abnormal facial features, mild recurrent sinopulmonary infections, and her endocrine history (including short stature with height in the 6th percentile), genetic testing was obtained. She was diagnosed with a heterozygous whole gene deletion of the TBX1 gene. Additional genetic evaluation demonstrated a 2.6-Mb microdeleted segment of the 22a11.2 region encompassing 62 genes. The patient was referred to cardiology for evaluation of cardiac involvement given a history of tachyarrhythmia. This case highlights challenges in diagnosis and the implications of a delayed diagnosis of 22.q11.2 DS. [ABSTRACT FROM AUTHOR]

Objective: 22q11.2 Deletion Syndrome (22q11DS) results in physical, cognitive, and behavioral issues. Although it is the most common microdeletion syndrome, there remains a high prevalence of delayed diagnosis. Its heterogeneous phenotypic presentation lead to differing considerations for early diagnostic identification. If initial symptomatology includes behavioral and cognitive disturbance, it is likely for such individuals to be referred first for neuropsychological testing before genetic testing. This case will expand upon diagnostic identification of 22q11DS. Method: A 12-year-old, 5-years educated, white female was seen for tele-neuropsychological evaluation due to COVID-19 restrictions in December 2020. Patient's mother reported concern regarding sudden and worsening behavioral changes including hallucinations, unusual affects, odd beliefs, academic decline, illegible handwriting, attention and memory issues, and behavioral problems in school to the point of removal. Results: Overall performance on the Meyers Neuropsychological Battery was severely impaired. See uploaded image file for specific test findings. Speech, affect, and behavior were notable during examination. Diagnoses included schizophrenia (provisional) and specific learning disorder with reading impairment (historical). Immediate neurology consultation was recommended. Later EEG, brain MRI, and CSF were unremarkable. Acute metabolic etiology was ruled out. Subsequent genetic testing revealed 22q11DS. Conclusions: Diagnostic identification of 22q11DS and resulting access to care management heavily depends on initial symptom presentation. In this specific case, the COVID-19 lockdown created barrier to sufficient services. This case expands upon knowledge of the cognitive profile of 22q11DS and calls upon increased awareness. Targeted improvement of neurocognition potentially protects against cognitive decline related to psychotic symptoms, and thus neuropsychologists play a vital role in referral to such resources. [ABSTRACT FROM AUTHOR]

Objective Autistic traits are associated with mental health difficulties and risk of suicidal risk behaviors among adolescents. Little is known about how autistic traits affect the mental health of adolescents with rare neurodevelopmental disorders (RNDs). The aim of this study was to investigate the relationship between autistic traits, mental health difficulties, and suicidal risk behaviors in adolescents with RNDs. Methods Parents (N  =   93) completed the Child Behavior Checklist, Social Communication Questionnaire, and Social Responsiveness Scale about their adolescent (M age = 13.1, SD  = 2.3, 62.4% females) with an RND (e.g. sex chromosome aneuploidies, Fragile X syndrome, 22q11.2 deletion syndrome). The data were analyzed with hierarchical logistic regression analysis. Results The prevalence of suicidal risk behaviors (16.1%) was similar to that reported among autistic youth and was higher among boys than girls. More autistic traits were associated with suicidal risk behaviors in bivariate analysis. In multivariate analysis, more anxiety/depressive symptoms were associated with more suicidal risk behaviors and externalizing problems associated with suicidal risk behaviors beyond autistic traits and anxiety/depressive symptoms. Conclusion Adolescents with RNDs are at risk of suicidal risk behaviors, especially those with higher levels of autistic traits, anxiety/depressive symptoms, and externalizing problems. Assessment of autistic traits, mental health difficulties, and suicide risk may be indicated for adolescents with RNDs to determine if corresponding intervention is needed. [ABSTRACT FROM AUTHOR]

In patients with critical left ventricular outflow tract obstruction but adequately sized ventricles, the treatment of choice is biventricular repair. Several options have been proposed, including neonatal Yasui or Ross–Konno operation. However, each of these procedures carries a high mortality risk, especially in syndromic neonates. Here, we report the case of a patient with 22q11.2 deletion syndrome and a diagnosis of interrupted aortic arch type B2, ventricular septal defect and left ventricular outflow tract obstruction. As a means to avoid high-risk neonatal surgery in this patient, we pursued a strategy of delayed biventricular repair involving initial hybrid Norwood palliation followed by a Yasui-type operation at 3 months. Although this strategy turned out to be successful, proactive monitoring for the development of ductal stent stenosis during follow-up after the hybrid procedure remains crucial to prevent hemodynamic complications such as cardiac failure and systemic hypoperfusion. [ABSTRACT FROM AUTHOR]

Schizophrenia is a chronic and disabling mental illness characterized by a disordered sense of self. Current theories suggest that deficiencies in the sense of control over one's actions (Sense of Agency, SoA) may underlie some of the symptoms of schizophrenia. However, it is not clear if agency deficits are a precursor or a result of psychosis. Here, we investigated full body agency using virtual reality in a cohort of 22q11 deletion syndrome participants with a genetic propensity for schizophrenia. In two experiments employing virtual reality, full body motion tracking, and online feedback, we investigated SoA in two separate domains. Our results show that participants with 22q11DS had a considerable deficit in monitoring their actions, compared to age-matched controls in both the temporal and spatial domain. This was coupled with a bias toward erroneous attribution of actions to the self. These results indicate that nonpsychotic 22q11DS participants have a domain general deficit in the conscious sensorimotor mechanisms underlying the bodily self. Our data reveal an abnormality in the SoA in a cohort with a genetic predisposition for schizophrenia, but without psychosis, providing evidence that deficits in delineation of the self may be a precursor rather than a result of the psychotic state. [ABSTRACT FROM AUTHOR]

Background Attention deficit and/or hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children with 22q11.2 deletion syndrome (22q11DS) and frequently persists into adulthood. Although medication with stimulant has been demonstrated to be highly effective in idiopathic ADHD, evidence in 22q11DS is still scarce. Previous studies have shown safety and effectiveness of methylphenidate (MPH) on core symptoms of ADHD as well as improvement of associated cognitive deficits. However, only a limited number of cognitive domains have been explored. Methods Twenty-three participants with 22q11DS and attention difficulties, aged 8–24 years, entered a clinical trial aiming to specify the effects of MPH on clinical symptoms, cognition, and daily-life behavior. The effects of treatment were compared with/without medication in a within-subject design. The trial included both participants naïve to the molecule and chronic users. Results Benefit from the treatment was demonstrated through a decrease in core ADHD symptoms, specifically inattention symptoms, and improvement of cognitive measures of attention and inhibition. Conversely, no significant change was found for other executive functions (such as cognitive flexibility, working memory, initiation), learning, or memory. Moreover, no significant improvement on ecological measures of daily-life executive functioning was found, possibly because of the short treatment period. We replicated safety, and although very frequent, side effects were of mild intensity and comparable with previous findings. Conclusions This study extends the current knowledge on the effects of MPH in patients with 22q11DS. Treatment was found to be effective for core ADHD symptoms and cognitive measures of attention and inhibition. [ABSTRACT FROM AUTHOR]

Background DiGeorge syndrome, also known as 'CATCH 22', is the most common deletion in humans and is one of the velocardiofacial syndromes. It is characterized by a specific facial phenotype, and structural and functional abnormalities in the cardiac and endocrine systems. One form of endocrine system dysfunction is hypocalcaemia, which causes arrhythmic events and can result in a transient loss of consciousness. We present a case highlighting the late diagnosis of DiGeorge syndrome in a patient with recurrent episodes of syncope due to suspected arrhythmic events secondary to hypocalcaemia. Case summary A 44-year-old woman was referred for further investigation of recurrent syncope episodes and documented transient QT-prolongation with hypocalcaemia. Previous detailed cardiological examination, including invasive procedures such as coronary angiography and cardiac magnetic resonance tomography, was unremarkable. Slight characteristic facial dysmorphia and transient hypocalcaemia were strongly suggestive of DiGeorge syndrome. The diagnosis was confirmed by genetic testing. Calcium substitution was initiated and no recurrent episodes of syncope or arrhythmic events were reported during 12 months of follow-up. Discussion Clinical presentation and time of manifestation of the DiGeorge syndrome varies widely depending on the mutation expression extent. An atypical disease course may delay the diagnosis and appropriate management of affected patients. In this case, confirmation of the diagnosis allowed the initiation of appropriate treatment, reducing the risk for further events. Given that syncope and arrhythmia can be the first and only manifestation of late-onset DiGeorge syndrome, specialists in adult cardiology need to be aware of this presentation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites world-wide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder. [ABSTRACT FROM AUTHOR]

The recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia. [ABSTRACT FROM AUTHOR]

In 2009, a federally funded clinical and research consortium ( PID- NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies ( PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency ( CVID), the most prevalent PID. [ABSTRACT FROM AUTHOR]

Thymic hypoplasia is a frequent feature of the 22q11.2 deletion syndrome, but we know little about patients' age-related thymic output and long-term consequences for their immune system. We measured the expression of T cell receptor rearrangement excision circles (TREC) and used flow cytometry for direct subtyping of recent thymic emigrant (RTE)-related T cells in 43 patients (aged 1–54 years; median 9 years) from all over Norway and in age-matched healthy controls. Thymic volumes were estimated by ultrasound in patients. TREC levels correlated well with RTE-related T cells defined by co-expression of CD3, CD45RA and CCR9 ( r = 0·84) as well as with the CD4+ and CD8+ T cell subtypes. RTE-related T cell counts also paralleled age-related TREC reductions. CD45RA+ T cells correlated well with absolute counts of CD4+ ( r = 0·87) and CD8+ ( r = 0·75) RTE-related T cells. Apart from CD45RA- T cells, all T cell subsets were lower in patients than in controls. Thymic volumes correlated better with RTE-related cells ( r = 0·46) than with TREC levels ( r = 0·38). RTE-related T cells and TREC levels also correlated well ( r = 0·88) in patients without an identifiable thymus. Production of RTEs is impaired in patients with a 22q11.2 deletion, and CCR9 appears to be a good marker for RTE-related T cells. [ABSTRACT FROM AUTHOR]

A subgroup of patients with 22q11·2 microdeletion and partial DiGeorge syndrome (pDGS) appears to be susceptible to non-cardiac mortality (NCM) despite sufficient overall CD4+ T cells. To detect these patients, 20 newborns with 22q11·2 microdeletion and congenital heart disease were followed prospectively for 6 years. Besides detailed clinical assessment, longitudinal monitoring of naive CD4+ and cytotoxic CD3+CD8+ T cells (CTL) was performed. To monitor thymic activity, we analysed naive platelet endothelial cell adhesion molecule-1 (CD31+) expressing CD45RA+RO-CD4+ cells containing high numbers of T cell receptor excision circle (TREC)-bearing lymphocytes and compared them with normal values of healthy children ( n = 75). Comparing two age periods, low overall CD4+ and naive CD4+ T cell numbers were observed in 65%/75%, respectively, of patients in period A (< 1 year) declining to 22%/50%, respectively, of patients in period B (> 1/< 7 years). The percentage of patients with low CTLs (< P10) remained robust until school age (period A: 60%; period B: 50%). Low numbers of CTLs were associated with abnormally low naive CD45RA+RO-CD4+ T cells. A high-risk (HR) group ( n = 11) and a standard-risk (SR) ( n = 9) group were identified. HR patients were characterized by low numbers of both naive CD4+ and CTLs and were prone to lethal infectious and lymphoproliferative complications (NCM: four of 11; cardiac mortality: one of 11) while SR patients were not (NCM: none of nine; cardiac mortality: two of nine). Naive CD31+CD45RA+RO-CD4+, naive CD45RA+RO-CD4+ T cells as well as TRECs/106 mononuclear cells were abnormally low in HR and normal in SR patients. Longitudinal monitoring of naive CD4+ and cytotoxic T cells may help to discriminate pDGS patients at increased risk for NCM. [ABSTRACT FROM AUTHOR]

The article describes the case of a 9-year-old male with DiGeorge syndrome and tetralogy of Fallot who developed increased fatigue with abdominal pain and intermittent emesis and was admitted in February 2014 with progressive cough and low-grade fevers. It details the case's final diagnosis, culture-negative infective endocarditis (IE) complicated by glomerulonephritis with positive serology testing for Bartonella henselae.

More than 11 genetic causes of severe combined immunodeficiency (SCID) have been identified, affecting development and/or function of T lymphocytes, and sometimes B lymphocytes and natural killer (NK) cells. Deletion of 22q11.2 is associated with immunodeficiency, although less than 1% of cases are associated with T–B + NK + SCID phenotype. Severe immunodeficiency with CHARGE syndrome has been noted only rarely Omenn syndrome is a rare autosomal recessive form of SCID with erythroderma, hepatosplenomegaly, lymphadenopathy and alopecia. Hypomorphic recombination activating genes 1 and 2 mutations were first described in patients with Omenn syndrome. More recently, defects in Artemis, RMRP, IL7Rα and common gamma chain genes have been described. We describe four patients with mutations in CHD7, who had clinical features of CHARGE syndrome and who had T–B + NK + SCID (two patients) or clinical features consistent with Omenn syndrome (two patients). Immunodeficiency in patients with DiGeorge syndrome is well recognized − CHARGE syndrome should now be added to the causes of T–B + NK + SCID, and mutations in the CHD7 gene may be associated with Omenn-like syndrome. [ABSTRACT FROM AUTHOR]

Background: The 22q11.2 deletion syndrome is a neurogenetic disorder that is associated with both physical anomalies and neurocognitive impairments. Deletion carriers have a greatly elevated risk of developing schizophrenia (SCZ); as such, it offers a compelling ‘high-penetrance’ model to explore the neuropathology of SCZ risk. Indeed, widespread structural alterations of both gray and white matter have been reported for 22q11.2 deletion carriers. Interestingly, there are also cases of duplications at the same gene locus. While less is known about the phenotype associated with 22q11.2 duplication, carriers also present physical and neurodevelopmental abnormalities, although they may have reduced risk of developing SCZ compared to the general population. The only study to date which looked at brain structure in duplication carriers found reciprocal effects of 22q11.2 deletion and duplication on cortical thickness and surface measurements. In the present study, we apply diffusion magnetic resonance imaging (MRI) to examine the white matter microstructure in both 22q11.2 deletion and duplication carriers. Methods: Multi-shell diffusion-weighted images were acquired on a 3 Tesla MRI scanner from 13 healthy control individuals (HC), 25 deletion carriers, and 18 22q11.2 duplication carriers. Images were preprocessed utilizing the Human Connectome Project (HCP) Minimal Preprocessing Pipeline v4.0.0. Free Water imaging was applied, which differentiates the diffusion signal into a free-water compartment and a tissue compartment. The output parameters are the free-water fractional volume (FW) and a free-water corrected diffusion tensor from which fractional anisotropy of the tissue (FAT) is calculated. We compared FAT and FW maps between 1) HC and 22q11.2 deletion carriers and 2) HC and 22q11.2 duplication carriers using Tract-Based Spatial Statistics (TBSS) and voxel-wise, non-parametric statistics (5000 permutations, threshold-free cluster enhancement, corrected for age and sex). Lastly, white matter clusters that displayed significant differences between 22q11.2 deletion or duplication and HC were extracted. We averaged FAT and FW values over these significant clusters for each individual and correlated with the scores of the Structured Interview for Prodromal Syndromes (SIPS). Results: 22q11.2 deletion carriers showed significant (p<0.05) FW reductions (72% of white matter skeleton) and FAT increase (8%) when compared to HC. In contrast, 22q11.2 duplication carriers displayed the opposite effect, with significant (p<0.05) widespread FW increase (51%) and FAT decrease (50%) when compared to HC. Both 22q11.2 deletion and duplication carriers scored higher on the SIPS than HC, with negative symptom score differences being the most pronounced (mean for HC= 1.36, mean for 22q11.2 duplication = 7.0, mean for 22q11.2 deletion =9.96, F=6.68, df=2, p<.003). FAT and FW were not associated with SIPS scores in 22q11.2 deletion syndrome. However, FAT was negatively correlated with the negative symptom score in 22q11.2 duplication carriers (Spearman rho=-.61, p<.009). Discussion: We observed opposing effects of gene-dosage on FAT and FW. While we did not see an association between WM measurements and psychotic symptoms in 22q11.2 deletion, there was an association of WM structure with negative symptoms in 22q11.2 duplication carriers. These findings highlight the importance of studying the influence of reciprocal chromosomal imbalance on white matter architecture. Ongoing longitudinal studies may help advance understanding of the role of microstructural white matter abnormalities in the emergence of neuropsychiatric symptoms. [ABSTRACT FROM AUTHOR]

Background: 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge syndrome or velo-cardio-facial syndrome) is characterized by increased vulnerability for neuropsychiatric symptoms, with approximately 30% of the individuals with the deletion developing schizophrenia. Clinically, deficits in executive function have been noted in this population, but the underlying neural processes are not well understood. Methods: Using high-density electrophysiology (EEG), we investigated the neural dynamics of inhibition of a prepotent response (a critical component of executive function) in individuals with 22q11.2DS with and without psychotic symptoms. Twenty-seven individuals with 22q11.2DS (14–35 years old, 14 with at least one psychotic symptom) and 27 age-matched neurotypical controls participated in a go/no-go task while EEG was recorded. Analyses were focused on the P3 go/no-go response and error-related positivity (Pe). Results: Behaviorally, individuals with 22q11.2DS were slower and unable to inhibit prepotent responses as the controls, with significantly more false alarms. Atypical inhibitory processing was confirmed by significantly reduced P3 no-go responses in the 22q11.2DS group. Such reductions were particularly marked in those with psychotic symptomatology. Pe was likewise significantly decreased (regardless of the presence of psychotic symptoms), suggesting impaired ability to register errors (i.e., false alarms) in 22q11.2DS. Both Pe and P3 correlated with clinical measures of inhibition (DKEFS and CPT). Discussion: To our knowledge, this is the first study looking at electrophysiological measures of response inhibition in 22q11.2DS. P3 and Pe reductions, which have also been shown in schizophrenia, suggest diminished error registration and awareness in 22q11.2DS and, possibly, a consequent difficulty in adjusting response strategies. [ABSTRACT FROM AUTHOR]

Chromosome 22q11.2 deletion syndrome is a common disorder characterized by thymic hypoplasia, conotruncal cardiac defect and hypoparathyroidism. Patients have a risk of infections and autoimmunity associated with T lymphocytopenia. To assess the immunological constitution of patients, the numerical changes and cytokine profile of circulating T cells were analysed by flow cytometry and real-time polymerase chain reaction (PCR). CD3+, CD4+, T cell receptor (TCR)αβ+ or CD8αα+ cell counts were lower, and CD56+ cell counts were higher in patients than in controls during the period from birth to adulthood. The ageing decline of CD3+ or CD4+ cell counts was slower in patients than in controls. The proportion of CD8αα+ cells increased in controls, and the slope index was larger than in patients. On the other hand, both the number and proportion of Vα24+ cells increased in patients, and the slope indexes tended to be larger than in controls. The positive correlation of the number of T cells with CD8αα+ cells was observed only in patients, and that with Vα24+ cells was seen only in controls. No gene expression levels of interferon (IFN)-γ, interleukin (IL)-10, transforming growth factor (TGF)-β, cytotoxic T lymphocyte antigen 4 (CTLA4) or forkhead box p3 (Foxp3) in T cells differed between patients and controls. There was no significant association between the lymphocyte subsets or gene expression levels and clinical phenotype including the types of cardiac disease, hypocalcaemia and frequency of infection. These results indicated that T-lymphocytopenia in 22q11.2 deletion patients became less severe with age under the altered composition of minor subsets. The balanced cytokine profile in the limited T cell pool may represent a T cell homeostasis in thymic deficiency syndrome. [ABSTRACT FROM AUTHOR]

Background More than 350 genetic disorders cause immune deficiencies; given the rarity of these conditions, in-depth study of infections associated with primary immune deficiencies (PID) requires extremely large sample sizes from broad populations. Using a large electronic health record (EHR) dataset, we linked clinical and microbiologic data to develop digital phenotypes for PID. Methods Using the Cerner HealthFacts EHR dataset from 2009 to 2017 we extracted clinical and microbiologic data for hospitalizations from patients <18 years old with ICD9/10 PID diagnoses and ≥1 positive culture for infection. Machine learning models were used to identify key features to predict PID diagnosis. Features included patient and hospitalization characteristics; infectious agent and infection site; and selected comorbidities. Model validation was done using the area under the receiver operating characteristic (AUC) curve. Results Overall 1316 patients with a PID were identified (Table 1). The 10 most common pathogens identified by PID are listed in Table 2. The models classified DiGeorge syndrome (positive predictive value 49%), functional disorders of polymorphonuclear neutrophils (PMN) (PPV 43%), and common variable immunodeficiency (CVID) (PPV 47%) better than combined immunodeficiency (CID) (PPV 20%); the overall true positive rate was 47% with an AUC of 0.73. Predictive features for each PID were as follows: CVID—having enteritis, hypertension, and pneumonia (Figure 1a); PMN—having hypoxia and hypertension (Figure 1b); DiGeorge syndrome—having congenital deformities and not having hypertension (Figure 1c); CID—finding Staphylococcus aureus in a wound or Escherichia coli in the blood were predictive of CID (Figure 1d). Conclusion Early models demonstrate some discrimination, specifically for more common PIDs (CVID) and those with highly identifying factors (DiGeorge syndrome). These models can be improved by including a wider array of clinical data, and they provide a first look at a new methodology to digitally phenotype PIDs for future diagnostic use. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine whether increased apoptosis in peripheral blood lymphocytes plays a role in T cell deficiency associated with DiGeorge anomaly. T cell subsets from a patient with DiGeorge anomaly were examined for the expression of Fas, FasL, Bcl-2 and Bcl-XL at the protein level with monoclonal antibodies, using dual-colour flow cytometry, and at the mRNA level in mononuclear cells by quantitative reverse transcriptase-polymerase chain reaction. In vitro spontaneous apoptosis was examined by propidium iodide staining and DNA fragmentation, using flow cytometry and gel electrophoresis, respectively. Fas and FasL expression, both at the level of protein and of mRNA, was increased, whereas Bcl-2 expression was decreased both at the level of protein and of mRNA. However, no difference in Bcl-XL expression was observed between the patient and an age-matched control. A significant proportion of both CD4+ and CD8+ T cells from the patients underwent spontaneous apoptosis, whereas almost no spontaneous apoptosis was observed in the age-matched control. These data suggest that spontaneous apoptosis in T lymphocytes, at least in part, may be responsible for T cell deficiency in DiGeorge anomaly. [ABSTRACT FROM AUTHOR]

The article presents a case study of a four-year old male who has DiGeorge syndrome, developmental delay and complex congenital heart disease. It mentions that the transthoracic echocardiogram conducted to the patient showed the existence of mobile echobright structure near the patient's xenograft valve. It discusses Cardiobacterium hominis which is seldom identified due to its slow growth characteristics.

Abstract: We report a rare case of neonatal biventricular repair of a right interrupted aortic arch (type B), with an aberrant left subclavian artery, ventricular septal defect and retroaortic innominate vein in a 4-week-old, 2.7kg neonate with DiGeorge syndrome. The patient had an unremarkable postoperative recovery. We discuss the anatomy of this rare congenital anomaly, its surgical implications and issues surrounding the adequacy of the left ventricular outflow tract. [Copyright &y& Elsevier]

Objective: 22q11.2 Deletion Syndrome, (DiGeorge Syndrome), is a genetic disorder which commonly causes heart defects, a submucosal cleft palate, and other health conditions, in addition to developmental delays. Individuals with DiGeorge Syndrome are more likely to have Attention-Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD), with research also supporting a high risk for developing schizophrenia in adulthood. Method: In this case study, a 22-year-old woman presented with DiGeorge Syndrome and trunkus arteriosus at the Department of Human Services (DHS) for employment services. Additionally, the patient's parents reported concerns about behavioral outbursts and emotional regulation difficulties for the last three years. The patient completed a full neuropsychological, cognitive, and emotional assessment battery to help understand any neurocognitive and psychological limitations in obtaining and maintaining employment. Results: On neurocognitive testing, she performed in the Severely Impaired range on measures of attention, processing speed, working memory, verbal memory, visual memory, visuospatial ability, motor functioning, and nonverbal problem solving. While performing in the Moderately Impaired range for tactile memory, verbal fluency, and cognitive flexibility. However, the patient exhibited a personal strength on the Verbal Comprehension Index of the Wechsler Adult Intelligence Scale—Fourth Edition (WAIS-IV). On emotional functioning testing, she did not display early signs of schizophrenia nor psychosis. However, the patient did express emotional and behavioral signs of ADHD and ASD. Conclusion: This case study emphasizes the need for neuropsychological testing and ongoing psychological monitoring for individuals with DiGeorge Syndrome, as it relates to treatment recommendations and planning. [ABSTRACT FROM AUTHOR]

Background: 22q11DS is the most common microdeletion with an incidence of 1:4000 live births. It is considered a genetic biological model for psychosis vulnerability: 25–28% of 22q11DS adults is affected by a psychotic disorder. Few data are available regarding functioning in 22q11DS. Our aim was to test the hypothesis that functioning is similar in 22q11DS psychotic and non-psychotic patients, and idiopathic schizophrenic subjects. We expected also a correlation between negative symptoms and functioning. Methods: Data come from Italian Network for Research on Psychoses for the Schizophrenic (SCZ, N=252) and Control groups (HC, N=110). 22q11DS psychotic (22q11DS_SCZ, N=21) and non-psychotic patients (22q11DS, N=23) were enrolled at Policlinico Umberto I, in Rome. The SLOF scale (Specific Levels of Functioning) and the Brief Negative Symptom Scale interview (BNSS) were employed. Results: The Global Functioning was significantly different between all groups but not between 22q11DS groups and SCZ. The multivariate analysis of variance showed the higher effect size for the Interpersonal Functioning, in which differences resulted significant between all groups, except for the comparison between 22q11DS-SCZ and SCZ. Differences between groups in BNSS were significant except for the post-hoc 22q11DSSCZ vs SCZ. Global and Interpersonal Functioning showed a significant negative correlation with BNSS scores in the three clinical groups. Discussion: 22q11DS-SCZ showed a severe deficit in Interpersonal Functioning, similar to that of idiopathic schizophrenia. 22q11DS showed a deficit in Interpersonal Functioning respect to control group, but less severe than psychotic groups. Our data suggest a common impairment shared among the clinical groups, that may be the functional correlate of an underlying neurobiological mechanism. [ABSTRACT FROM AUTHOR]

Background The TBX1 gene encodes the T-box 1 protein that is a transcription factor involved in development. Haploinsufficiency of the TBX1 gene is reported to cause features similar to DiGeorge syndrome. The TBX1 gene is located within the DiGeorge syndrome region, and studies support that the TBX1gene is responsible for most of the features of the phenotype of hemizygous deletion of chromosome 22q11.2. In this study, we report a family of 4 (a father with 3 children) who presented with congenital hypoparathyroidism and hypocalcemia, facial asymmetry, deafness, normal intelligence, and no cardiac involvement. Methods We performed whole genome sequencing, computational structural analysis of the mutants, and gene expression studies for all affected family members. Results Whole genome sequencing revealed a paternal inherited novel heterozygous variant, c.1158_1159delinsT p.(Gly387Alafs*73), in the exon 9 isoform C TBX1 gene, causing a loss of nuclear localization sequence (NLS) and transactivation domain (TAD) with no change in gene expression and resulted in a DiGeorge-like phenotype. Conclusion A pathogenic variant in the TBX1 gene exon 9 C that predicted to cause a loss in the NLS region and most of TAD leads to variable features of hypoparathyroidism, distinctive facial features, deafness, and no cardiac involvement. In addition, our report and previous reports indicate the presence of a wide phenotypic spectrum of TBX1 genetic variants and the consistent absence of cardiac involvement in the case of pathogenic variants on exon 9 isoform C TBX1 gene. [ABSTRACT FROM AUTHOR]

Background We noted a recent increase in the number of patients with CMV viremia among immunocompromised children at our institution. The study was undertaken to determine the prevalence of CMV viremia and to evaluate factors associated with the development of antiviral drug resistance. Methods A retrospective study of immunocompromised hosts 0–21 years of age who had CMV viremia (2007–2017). We collected demographic data as well as details of antiviral therapy and resistance testing. Results A total of 31 patients were identified including 10 (32%) during the last 2 years. The age range was 3 months to 20 years (median 12.6 years); 23 (74%) were male and 12 (39%) were African American. Among the 31 patients, 18 had hematopoietic stem cell transplantation, 5 had primary immunodeficiency (2 common variable immunodeficiency, 1 SCID, 1 Langerhans cell histiocytosis, 1 DiGeorge syndrome), 4 had malignancies receiving chemotherapy, 3 with heart transplantation and one 17 year old with newly diagnosed HIV infection who presented with CMV pneumonia and viremia. Antiviral resistance testing was performed on 7 CMV isolates: 5 due to persistent viremia (> 1 months) despite treatment, and 2 prior to starting antiviral therapy. CMV resistance was identified in 3 patients including 2 with CVID and one with Hodgkin's disease status post bone marrow transplantation. The 2 CVID patients had other comorbidities including chronic diarrhea and malabsorption and were TPN dependent. Both were diagnosed with CMV colitis and one also had pneumonitis. One had received a prolonged oral valganciclovir course (> 1 year) prior to diagnosis of resistance and the other received long-term intermittent oral valganciclovir courses. The patient with Hodgkin's disease received a prolonged IV ganciclovir course. All 3 tested positive for UL97 mutation and one had both UL97/UL54 gene mutations. Conclusion Most of our patients with CMV viremia were transplant patients. Antiviral drug resistance was detected among 3 of 31 (10%) of our patients during the study period. Two had malabsorption that may have resulted in sub-therapeutic blood levels. Treatment with oral valganciclovir should be avoided in patients with poor gut absorption because it may increase risk of drug resistance. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]