DiGeorge Syndrome Patients Research Articles

The Outcomes of Cardiac Surgery in Children With DiGeorge Syndrome in a Single Center Experience: A Retrospective Cohort Study.

Background DiGeorge syndrome, a common genetic microdeletion syndrome, is associated with multiple congenital anomalies, including congenital cardiac diseases. This study aims to identify the short and midterm outcomes of cardiac surgery performed on children with DiGeorge syndrome. Methods A retrospective cohort study was conducted between the period of 2018-2022, which included children divided into two groups with a 1:2 ratio. Group one included DiGeorge syndrome patients who were diagnosed using fluorescence in situ hybridization (FISH). Group two included the control group of patients who were clear of genetic syndromes. The two groups were matched based on similar cardiac surgery, age of surgery, and Risk Adjustment in Congenital Heart Surgery (RACHS-1) score. The two groups were compared based on the demographical data and postoperative complications. Results The study consisted of 81 children; 27 were DiGeorge syndrome patients, and 54 were in the control group. DiGeorge syndrome patients showed an increase in mechanical ventilation duration (p=0.0047), intensive care unit (ICU) length of stay (p=0.0012), and hospital length of stay (p=0.0391). Moreover, they showed an increased risk for bacteremia (p=0.0414), ventilator-associated pneumonia (VAP; p=0.0036), urinary tract infections (UTI; p=0.0064), and surgical site infection (SSI; p≤0.0001). They were also more susceptible to postoperative seizures (p=0.0049). Furthermore, patients with DiGeorge syndrome had a higher prevalence of congenital renal anomalies. However, there was no mortality in either group. Conclusion This study shows a variability in the postoperative outcomes between the two groups. The study demonstrates that patients with DiGeorge syndrome have higher risks of infections and longer hospital stayduring the postoperative period. Further research with a larger sample is needed to confirm our findings.

Neuroinflammation and Oxidative Stress in Individuals Affected by DiGeorge Syndrome

DiGeorge syndrome (DGS) is a rare genetic disease caused by microdeletions of the 22q11.2 region (DGS1). A haploinsufficiency at 10p level has been proposed also as a DGS cause (DGS2). Clinical manifestations are variable. The most frequent features are thymic hypoplasia or aplasia with consequent immune deficiency, cardiac malformations, hypoparathyroidism, facial and palatine abnormalities, variable degrees of cognitive impairment and psychiatric disorders. The specific aim of this descriptive report is to discuss the correlation between oxidative stress and neuroinflammation in DGS patients with microdeletions of the 22q11.2 region. The deleted chromosomic region maps various genes involved in mitochondrial metabolisms, such as DGCR8 and TXNRD2, that could lead to reactive oxygen species (ROS) increased production and antioxidant depletion. Furthermore, increased levels of ROS in mitochondria would lead to the destruction of the projection neurons in the cerebral cortex with consequent neurocognitive impairment. Finally, the increase in modified protein belonging to the family of sulfoxide compounds and hexoses, acting as inhibitors of the IV and V mitochondria complex, could result in direct ROS overproduction. Neuroinflammation in DGS individuals could be directly related to the development of the syndrome's characteristic psychiatric and cognitive disorders. In patients with psychotic disorders, the most frequent psychiatric manifestation in DGS, Th-17, Th-1 and Th-2 cells are increased with consequent elevation of proinflammatory cytokine IL-6 and IL1β. In patients with anxiety disorders, both CD3 and CD4 are increased. Some patients with autism spectrum disorders (ASDs) have an augmented level of proinflammatory cytokines IL-12, IL-6 and IL-1β, while IFNγ and the anti-inflammatory cytokine IL-10 seem to be reduced. Other data proposed that altered synaptic plasticity could be directly involved in DGS cognitive disorders. In conclusion, the use of antioxidants for restoring mitochondrial functionality in DGS could be a useful tool to protect cortical connectivity and cognitive behavior.

Characterization of thymic epithelial cell and thymocyte function and development in patients with thymic defects using scRNAseq profiling

Abstract The interaction between thymocytes and thymic epithelial cells (TEC) in the thymus is critical for the correct function and maturation of both cell populations and for the development of a diverse repertoire of non-self-reactive T-cell lymphocytes. Limited information is available on lympho-stromal crosstalk in the thymus of patients carrying thymic defects. We have previously shown that thymic tissues from DiGeorge syndrome (DGS) and Down syndrome (DS) patients have alterations in architecture and TEC composition, leading to altered T-cell development. Based on these results, we are performing single cell RNAseq (scRNAseq) to explore the transcriptional landscape of both stromal and hematopoietic components in the human thymus. Thanks to a collaboration with the pediatric cardiothoracic surgery center at the Children’s National Medical Center in Washington D.C., we have access to discarded thymic samples obtained from pediatric patients with partial DGS and DS, and from patients without immune defects. Preliminary results of scRNAseq analysis comparing tissues from normal donors and DS patients revealed a different distribution of cell subsets in both hematopoietic and stromal compartments, with several pathways differentially regulated, such as stress and metabolic processes. Additionally, we established a collaboration with the Thoracic and Gastrointestinal Malignancies Branch at the National Cancer Institute and are evaluating samples obtained from resected thymic epithelial tumors. Integration of data obtained from normal and diseased thymic tissue will provide novel insights into the function and development of the human thymus that could be helpful in the clinical management of patients with thymic defects. This research was supported by the Intramural Research Programs of the NIAID and the NCI (Center for Cancer Research), NIH

Generation of human induced pluripotent stem cell lines derived from four DiGeorge syndrome patients with 22q11.2 deletion

DiGeorge syndrome (22q11.2 deletion syndrome, or CATCH22 syndrome), caused by hemizygous deletion of chromosome 22q11.2, results in the poor development of multiple organs. Here we have generated DiGeorge syndrome-specific human induced pluripotsnt stem cells (hiPSCs) derived from four patients. These established hiPSC lines showed self-renewal and pluripotency and carried a hemizygous deletion in 22q11.2. Since the molecular pathogenesis of DiGeorge syndrome caused by the 22q11.2 deletion is largely unknown, these cell resources will be useful for recapitulating disease phenotypes and for developing new therapies for DiGeorge syndrome.

Relationship Between Severity of T cell Lymphopenia and Immune Dysregulation in Patients With DiGeorge Syndrome (22q11.2 Deletions and/or Related TBX1 Mutations): A USIDNET Study

To evaluate if the severity of T-cell lymphopenia is associated with immune dysregulation, such as autoimmunity and asthma, in patients with DiGeorge syndrome (DGS) and/or TBX1 mutation.In this study, researchers included 415 patients with DGS and/or TBX1 mutations from the US Immunodeficiency Network registry. Patients with complete and atypical complete DGS were excluded. The median age was 4.6 years (range: 0–45 years).This was a retrospective analysis of 415 patients with DGS and/or TBX1 mutations from the US Immunodeficiency Network registry. Patients were stratified on the basis of severity of initial absolute CD3+ T cells. The rate of infections, autoimmunity, and atopic disease were compared by using χ2 tests and multivariate logistic regression.In this DGS cohort, the median absolute CD3+ T-cell count was 1424 (range: 85–6371 cells/μl). Among the 415 DGS patients, 25% reported congenital heart disease, 4.1% reported autoimmunity, and 6.7% reported asthma. Absolute CD3 counts were lower in those with cardiac disease (P < .001). Patients with absolute CD3+ T cells <50% of age-adjusted normal values were more likely to have reported autoimmunity (odds ratio: 7.56; 95% confidence interval: 1.58 to 36.17; P = .01) and asthma (odds ratio: 4.5; 95% confidence interval: 1.06 to 18.93; P = .04) when compared with those with normal T cell counts. The most commonly reported autoimmune conditions were thyroid disease and cytopenias. Patients with reported autoimmunity more frequently had low CD19+ B cells (P = .002) and low immunoglobulin G (P = .005), when compared with those without autoimmunity. There was no association noted between low CD3+ T cells and immunoglobulin levels or infection rates.Patients with DGS and absolute CD3+ T cells <50% of age-adjusted normal levels had a higher odds of developing autoimmunity and/or asthma, when compared with those with normal T cell counts.Although it is well known that DGS increases the risk for autoimmunity and atopy, in this study, the authors investigated the association between the severity of T-cell lymphopenia and odds of autoimmunity and atopy. Patients with absolute CD3+ T cells <50% of age-adjusted normal levels had a significantly higher odds of developing autoimmunity and/or asthma. This information is useful to providers because it helps us identify those at higher risk for developing autoimmunity and/or asthma and allows us to heighten our surveillance in this population, especially because autoimmunity and/or asthma had increasing frequency with advancing age. This was a large study of DGS patients nationally; however, it was limited by the nature of registry data, which had variable areas of missing data.

Plasma cells are essentially absent in the luminal gastrointestinal tract of patients with “complete” 22q11.2 deletion syndrome (DiGeorge syndrome)

Gastrointestinal symptoms are commonly reported in patients with 22q11.2 deletion syndrome or DiGeorge syndrome (DGS) in addition to the dominant cardiac manifestations and immunodeficiency. But literature providing specific morphologic details of the gastrointestinal tract pathology is very limited. Here, we provide the first comprehensive morphologic description of the luminal gastrointestinal tract changes in patients with DGS. Cytogenetically confirmed DGS patients were identified, clinical and laboratory data were reviewed to determine the severity of immunodeficiency, and patients were stratified into mildly immunocompromised, that is, partial DiGeorge anomaly or severely immunosuppressed, that is, complete DiGeorge anomaly groups. Gastrointestinal tract biopsies from these patients were retrospectively reviewed and compared with those from controls without the history of DGS. Patients with immunosuppressed DGS showed a near complete absence of plasma cells in the stomach, duodenum, and colon lamina propria by hematoxylin and eosin evaluation. Immunohistochemistry for CD138 used to highlight plasma cells confirmed this finding. The notable absence of plasma cells adds to the existing knowledge of the pathophysiology underlying DGSand expands the differential diagnostic considerations for this finding, which has been previously described in common variable immunodeficiency. It also provides a useful morphologic marker observable by the readily accessible light microscopy. Second, patients with DGS showed a mild increase in epithelial cell apoptosis in their colon. This finding is significant because of its overlap with morphologic features of gastrointestinal graft versus host disease as thymus transplantation is being used as a treatment option for patients with complete DGS.

Metabolic Parameters in Patients with Prader-Willi Syndrome and DiGeorge Syndrome with Respect to Psychopathological Manifestation.

PurposeThe purpose of our study was to compare the metabolic parameters in two genetic syndromes with a proven high risk of developing psychiatric comorbidities. These comorbidities, especially mood and psychotic disorders, may be associated with a risk of obesity, type 2 diabetes and other components of metabolic syndrome regardless of antipsychotic treatment.Patients and MethodsTwo groups of children diagnosed with Prader - Willi syndrome (PWS) (n = 20) and DiGeorge syndrome (DGS) (n = 18), aged 7–18 years, were enrolled. Behavioral symptoms and co-occurring psychopathological symptoms were assessed using the Child Behavior Checklist (CBCL). The levels of following biochemical parameters were measured: glucose, insulin, high-sensitivity C-reactive protein, total cholesterol, low- and high-density lipoproteins (LDL and HDL), triglycerides and non-HDL cholesterol. Additionally, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated.ResultsThere were significantly higher levels of insulin and non-HDL in patients with PWS compared to those with DGS. The scores of four CBCL subscales (social problems, thought problems, delinquent behavior and aggressive behavior) were significantly higher in PWS patients. Higher scores of the CBCL-thought problems were associated with significantly higher levels of insulin as well as HOMA-IR.ConclusionPatients with PWS seem to be more prone to develop subclinical metabolic dysregulation, in terms of elevated non-HDL levels and insulin levels, compared to DGS patients. Altered insulin sensitivity, present in both groups, even though it is not a specific risk factor, might be related to thought problems associated with psychosis.

Phenotypical T Cell Differentiation Analysis: A Diagnostic and Predictive Tool in the Study of Primary Immunodeficiencies.

Multiparametric flow cytometry (MFC) represents a rapid, highly reproducible, and sensitive diagnostic technology for primary immunodeficiencies (PIDs), which are characterized by a wide range of T cell perturbations and a broad clinical and genetic heterogeneity. MFC data from CD4+ and CD8+ T cell subsets were examined in 100 patients referred for Primary Immunodeficiencies to our center. Naïve, central memory, effector memory, and terminal effector memory cell differentiation stages were defined by the combined expression CD45RA/CD27 for CD4 and CD45RA/CCR7 for CD8. Principal component analysis (PCA), a non-hypothesis driven statistical analysis, was applied to analyze MFC data in order to distinguish the diverse PIDs. Among severe lymphopenic patients, those affected by severe combined and combined immunodeficiency (SCID and CID) segregated in a specific area, reflecting a homogenous, and a more severe T cell impairment, compared to other lymphopenic PID, such as thymectomized and partial DiGeorge syndrome patients. PID patients with predominantly antibody defects were distributed in a heterogeneous pattern, but unexpectedly PCA was able to cluster some patients' resembling CID, hence warning for additional and more extensive diagnostic tests and a diverse clinical management. In conclusion, PCA applied to T cell MFC data might help the physician to estimate the severity of specific PID and to diversify the clinical and diagnostic approach of the patients.

Identifying Primary Immune Deficiencies in Patients with Autoimmune Cytopenias

Objective: The purpose of this study is to increase awareness and improve diagnosis of primary immune deficiency (PID) in the heterogenous group of patients with autoimmune cytopenia (AIC) by identifying clinical characteristics and laboratory biomarkers that distinguish PID patients from patients with AIC alone. This is especially relevant in genetically-defined PIDs which may be resistant to conventional therapy and mechanism-based treatment approach is required. Evans syndrome, defined by multi-lineage autoantibodies (two or more positive anti-platelet, anti-neutrophil, or direct Coombs test) is a known risk factor for PID; therefore we also investigate the incidence of PID in a broad cohort of AIC patients with single and multi-lineage cytopenias. Methods: Patients with autoimmune cytopenias (autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), or autoimmune neutropenia (AIN)) were referred to our Immune Dysregulation clinical team and prospectively enrolled in the study period of 2016-2019. Detailed immune phenotyping (IgG, IgA, IgM, lymphocyte subsets, vaccine titers, lymphocyte proliferation to mitogens/antigens), serum lipopolysaccharide (LPS) and autoantibodies were measured and/or collected by chart review and genetic testing for PID was pursued. Results: From 2016 to 2019, 78 patients were enrolled to our study. The patients were predominantly children (ages 1-82 years, average age 16.82 years). Of 78 patients with AIC, 48 (61%) were diagnosed with underlying PID based on immune phenotyping and/or genetic testing. Of 39 patients with genetic testing to date, 19 (49%) have been diagnosed with genetically-defined PID (pathogenic variants in CTLA-4, NFKB1, ALPS-related genes, WAS, POLE-1, PI3K, CYBB, or 22q11 [partial DiGeorge syndrome]); the remainder were classified as combined immune deficiency or common variable immune deficiency based on immune phenotyping; an additional two patients were classified as ALPS based on clinical history/flow cytometry/family history of ALPS. Lymphocyte subsets (CD4+ T, CD8+ T, CD19+ B, CD56+ NK) and immune globulins (IgG, IgA, IgM) tended to be lower in AIC-PID patients vs AIC-only (p&lt;0.05). Evans syndrome was more commonly found in AIC-PID patients (13/31, 42%) compared to AIC-only (4/42, 10%). LPS was significantly elevated in the serum of AIC patients compared to healthy controls (mean 719 vs 87 pg/mL, p&lt;0.001). Excluding partial DiGeorge syndrome patients (average LPS 222pg/mL), LPS levels were significantly higher in genetically-defined untreated PID patients (average 1463 pg/mL) vs. other PID (average 444 pg/mL) (p=0.02) or patients with AIC alone (average 667 pg/mL) (p=0.03). Studies are ongoing on specific subsets that are linked to immune dysregulation (T-regulatory cells, double negative T cells, T follicular helper cells). Conclusions: An unexpectedly high fraction of patients with AIC were identified with underlying PID in our Immune Dysregulation program. Routine basic immune evaluation with immunoglobulin levels and lymphocyte subsets expedited diagnosis of PID. Genetic evaluation distinguished a group of patients with AIC-PID and highly elevated LPS level, reflecting high bacterial load, and this may distinguish them from the rest of patients with AIC. The source of bacterial LPS can be multifactorial and is yet to be determined. Our studies continue focusing on biomarkers that can be applied to the heterogenous group of patients with AIC. This will allow early detection and timely initiation of targeted therapies. Disclosures No relevant conflicts of interest to declare.

Immune system defects in DiGeorge syndrome and association with clinical course.

We evaluated 18 DiGeorge syndrome (DGS) patients and aimed to investigate the immunological changes in this population. DGS patients with low naive CD4+ T and CD8+ T cells were defined as high-risk (HR) patients, whereas patients with normal numbers of naive CD4+ and CD8+ T cells were defined as standard risk (SR) patients. Level of serum IgM, CD3+ T cell counts and percentages of class-switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism were detected significantly higher in HR group. Patients with reduced percentages of class-switched B cells had earlier onset of infection, lower blood IgM, lower CD4+ and CD8+ T counts than patients with normal class-switched memory B cells. Decreased levels of IgM were associated with low numbers of naive CD4+ and recent thymic emigrants T cells. Monitoring the immune changes of patients with DGS would be useful to predict the severe phenotype of disease.

Follicular Helper T Cells in DiGeorge Syndrome.

DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia. Most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, such as autoimmune thrombocytopenia. B cells in DiGeorge syndrome show impaired maturation, with low switched-memory B cells and a wide spectrum of antibody deficiencies or dysgammaglobulinemia, presumably due to impaired germinal center responses. We set out to evaluate circulating follicular helper T cells (cTFHs) in DiGeorge syndrome, as markers of T–B interaction in the germinal centers in a cohort of 17 patients with partial DiGeorge and 21 healthy controls of similar age. cTFHs were characterized as CXCR5+CD45RA− CD4+ T cells using flow cytometry. We verify previous findings that the population of memory CD4+ T cells is relatively increased in diGeorge patients, corresponding to low naïve T cells and impaired T cell production in the thymus. The population of CXCR5+ memory CD4+ T cells (cTFHs) was significantly expanded in patients with DiGeorge syndrome, but only healthy controls and not DiGeorge syndrome patients showed gradual increase of CXCR5 expression on cTFHs with age. We did not observe correlation between cTFHs and serum IgG levels or population of switched memory B cells. There was no difference in cTFH numbers between DiGeorge patients with/without thrombocytopenia and with/without allergy. Interestingly, we show strong decline of PD1 expression on cTFHs in the first 5 years of life in DiGeorge patients and healthy controls, and gradual increase of PD1 and ICOS expression on CD4− T cells in healthy controls later in life. Thus, here, we show that patients with DiGeorge syndrome have elevated numbers of cTFHs, which, however, do not correlate with autoimmunity, allergy, or production of immunoglobulins. This relative expansion of cTFH cells may be a result of impaired T cell development in patients with thymic dysplasia.

Use of Array Comparative Genomic Hybridization for the Diagnosis of DiGeorge Syndrome in Saudi Arabian Population

DiGeorge syndrome (DGS) is a genetic disorder known as a clinically variable syndrome with over 180 associated phenotypic features. It is caused by a common human deletion in the 22q11.2 chromosomal region and currently is affecting approximately 1 in 4,000 individuals. Despite the prevalence of inherited diseases mainly due to consanguineous marriages, the current diagnosis of DGS in Saudi Arabia is mainly based on conventional high-resolution chromosome banding (karyotyping) and FISH techniques. However, advanced genome-wide studies for detecting microdeletions or duplications across the whole genome are needed. The aim of this study is to implement and use aCGH technology in clinical diagnosis of the 22q11.2 deletion in Saudi Arabian DGS patients and to confirm its effectiveness compared to conventional FISH and chromosome banding techniques. Thirty suspected DGS patients were assessed for chromosome 22q11.2 deletion using high-resolution G-banding, FISH, and aCGH. The aCGH results were compared with those obtained by the other 2 cytogenetic techniques. G-banding detected the 22q11.2 deletion in only 1 patient in the cohort. Moreover, it detected additional chromosomal aberrations in 3 other patients. Using FISH, allowed for detection of the 22q11.2 deletion in 2 out of 30 patients. Interestingly, the use of aCGH technique showed deletions in the chromosome 22q11.2 region in 8 patients, indicating a 4-fold increase in diagnostic detection capacity compared to FISH. Our results show the effectiveness of aCGH to overcome the limitations of FISH and G-banding in terms of diagnostic yield and allow whole genome screening and detection of a larger number of deletions and/or duplications in Saudi Arabian DGS patients. Except for balanced translocations and inversions, our data demonstrate the suitability of aCGH in the diagnostics of submicroscopic deletion syndromes such as DGS and most chromosomal aberrations or complex abnormalities scattered throughout the human genome. Our results recommend the implementation of aCGH in clinical genomic testing in Saudi Arabia to improve the diagnostic capabilities of health services while maintaining the use of conventional cytogenetic techniques for subsequent validation or for specific and known aberrations whenever required.

Clinical diagnosis of tetralogy of Fallot children with concurrent DiGeorge syndrome

Objective To explore the clinical diagnosis of tetralogy of Fallot(TOF) children with concurrent DiGeorge syndrome(DGS). Methods Retrospective analyses were conducted for the clinical characteristics of 715 TOF children with concurrent DGS at Henan Provincial People's Hospital and the Third Affiliated Hospital of Zhengzhou University from January of 2008 to October of 2014.Among them, there were 78 definite cases of thymic aplasia(DGS group), including 45 boys and 33 girls with an age range of(9.12±4.35) months and a body mass range of(7.28±2.34) kg.And the remainder was designated as non-DGS group(NDGS group), including 387 boys and 250 girls with an age range of(8.21±5.61) months and a body mass range of(8.19±3.47) kg.In DGS group, genetic screening uncovered 10 cases of chromosome 22q11.2 gene deletion.And based upon this result, DGS group was further divided into genetic and clinical diagnosis subgroups.The genetic diagnosis group had 10 cases, including 6 boys and 4 girls with an age range of(8.12±4.15) months and a body mass range of(6.28±2.74) kg, the clinical diagnosis group had 68 cases, including 39 boys and 29 girls with an age range of(8.19±4.37) months and a body mass range of(7.05±2.39) kg. Results No statistical difference existed in age, body mass or preoperative developmental status of pulmonary vasculature between DGS group and NDGS group(P>0.05). And the preoperative incidence of recurrent pneumonia was obviously higher in DGS group than that in NDGS group(P 0.05). And an inter-group comparison of T lymphocyte immunity defect had no statistical difference(P>0.05). The duration of on-machine and intensive care unit stay was markedly longer in DGS group than that in NDGS group(P 0.05). And an inter-group comparison of T lymphocyte immunity defect had no statistical difference(P>0.05). Conclusions With diverse clinical manifestations, DGS patients may have non-specific findings of cellular immunity defect, hypocalcemia or facial malformation.TOF children with concurrent thymic aplasia should raise an alert so that effective interventions may be adopted to boost their long-term quality of life. Key words: DiGeorge syndrome; Tetralogy of Fallot; Clinical features

Low marginal zone-like B lymphocytes and natural antibodies characterize skewed B-lymphocyte subpopulations in del22q11 DiGeorge patients

PurposePatients with DiGeorge syndrome suffer from T-lymphopenia. T-cells are important for the maturation and regulation of B-cell function. Our aim was to characterize the B-cell compartment in DiGeorge syndrome patients. MethodsB-cell subset phenotypization using flow cytometry. Serum BAFF (B-cell activating factor) and serum anti-alpha-galactosyl IgM measurement using ELISA. Serum IgG measurement using nephelometry. ResultsWe observed a significantly increased number of naïve B-cells and decreased number of switched memory B-cells in DiGeorge patients. Furthermore, we observed increased BAFF levels and a trend toward hypergammaglobulinemia later in life. Surprisingly, we detected a decrease in marginal zone-like (MZ-like) B-cells and natural antibodies in DiGeorge patients. ConclusionThe maturation of B-cells is impaired in DiGeorge patients, with high naïve and low switched memory B-cell numbers being observed. There is a clear trend toward hypergammaglobulinemia later in life, coupled with increased serum BAFF levels. Surprisingly, the T-independent humoral response is also impaired, with low numbers of MZ-like B-cell and low levels of anti-alpha-galactosyl IgM natural antibodies being detected.

Post-childhood Presentation and Diagnosis of DiGeorge Syndrome.

The diversity of clinical presentations makes the diagnosis of DiGeorge syndrome (DGS) a diagnostic challenge. The objective of our study was to report the clinical presentation of DGS in the post-childhood period. A retrospective study, investigating patients diagnosed clinically and genetically with DGS at Sheba Medical Center during the period of 2010-2013. Post-childhood period was defined as age >10 years. During the study period, 29 patients were diagnosed with DGS. Nine (31%) patients with DGS were diagnosed in their post-childhood period. The basis for clinical suspicion was diverse. However, once the suspicion was brought to attention, additional symptoms consistent with DGS were noted at up to 88% of patients who presented characteristic of facial features and developmental delay. Our research shows that diagnosing DGS patients in the post-childhood period is not uncommon. Characteristic facial features and developmental delay, although not leading presenting symptoms, are found very frequently in patients with DGS.

DiGeorge syndrome who developed lymphoproliferative mediastinal mass.

DiGeorge syndrome is an immunodeficient disease associated with abnormal development of 3rd and 4th pharyngeal pouches. As a hemizygous deletion of chromosome 22q11.2 occurs, various clinical phenotypes are shown with a broad spectrum. Conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia are the classic triad of DiGeorge syndrome. As this syndrome is characterized by hypoplastic or aplastic thymus, there are missing thymic shadow on their plain chest x-ray. Immunodeficient patients are traditionally known to be at an increased risk for malignancy, especially lymphoma. We experienced a 7-year-old DiGeorge syndrome patient with mediastinal mass shadow on her plain chest x-ray. She visited Severance Children's Hospital hospital with recurrent pneumonia, and throughout her repeated chest x-ray, there was a mass like shadow on anterior mediastinal area. We did full evaluation including chest computed tomography, chest ultrasonography, and chest magnetic resonance imaging. To rule out malignancy, video assisted thoracoscopic surgery was done. Final diagnosis of the mass which was thought to be malignancy, was lymphoproliferative lesion.

Milk-alkali-induced Pancreatitis in a Chronically Hypocalcemic Patient with DiGeorge Syndrome

BackgroundPancreatitis is a common diagnosis in the emergency department (ED), and milk-alkali syndrome (MAS) is an uncommon etiology for pancreatitis. MAS is caused by increased calcium and alkali ingestion, causing hypercalcemia accompanied by metabolic alkalosis and renal failure. Once considered rare, MAS is an increasingly common cause of hypercalcemia. Awareness of the resurgence of this syndrome is important for emergency physicians when recalling the causes of renal failure and pancreatitis. We present a case of pancreatitis and acute renal failure (ARF) in a chronically hypocalcemic DiGeorge syndrome patient, resulting from hypercalcemia secondary to excessive ingestion of calcium carbonate tablets. Case ReportA patient with DiGeorge syndrome and chronic abdominal pain due to gastroesophageal reflux disease (GERD) presented to our ED for severe abdominal pain. He reported nausea and vomiting, as well as epigastric pain that seemed worse than his typical pain. Laboratory evaluation revealed pancreatitis and ARF, although the patient had no prior history of these conditions. Upon further questioning, his mother divulged that the patient had been taking large quantities of calcium carbonate tablets for his worsening GERD symptoms. The patient was admitted to the intensive care unit where his pancreatitis and ARF eventually resolved as his calcium levels returned to his baseline. Why Should an Emergency Physician Be Aware of This?MAS is a relatively uncommon diagnosis, but can lead to serious sequelae such as pancreatitis and ARF. Questioning the patient about calcium ingestion is an important facet to the diagnosis and work-up of pancreatitis and ARF. Recognition of this etiology can improve patient outcomes and prevent recurrences.

The TREC/KREC assay for the diagnosis and monitoring of patients with DiGeorge syndrome.

DiGeorge syndrome (DGS) presents with a wide spectrum of thymic pathologies. Nationwide neonatal screening programs of lymphocyte production using T-cell recombination excision circles (TREC) have repeatedly identified patients with DGS. We tested what proportion of DGS patients could be identified at birth by combined TREC and kappa-deleting element recombination circle (KREC) screening. Furthermore, we followed TREC/KREC levels in peripheral blood (PB) to monitor postnatal changes in lymphocyte production.MethodsTREC/KREC copies were assessed by quantitative PCR (qPCR) and were related to the albumin control gene in dry blood spots (DBSs) from control (n = 56), severe immunodeficiency syndrome (SCID, n = 10) and DGS (n = 13) newborns. PB was evaluated in DGS children (n = 32), in diagnostic samples from SCID babies (n = 5) and in 91 controls.ResultsAll but one DGS patient had TREC levels in the normal range at birth, albeit quantitative TREC values were significantly lower in the DGS cohort. One patient had slightly reduced KREC at birth. Postnatal DGS samples revealed reduced TREC numbers in 5 of 32 (16%) patients, whereas KREC copy numbers were similar to controls. Both TREC and KREC levels showed a more pronounced decrease with age in DGS patients than in controls (p<0.0001 for both in a linear model). DGS patients had higher percentages of NK cells at the expense of T cells (p<0.0001). The patients with reduced TREC levels had repeated infections in infancy and developed allergy and/or autoimmunity, but they were not strikingly different from other patients. In 12 DGS patients with paired DBS and blood samples, the TREC/KREC levels were mostly stable or increased and showed similar kinetics in respective patients.ConclusionsThe combined TREC/KREC approach with correction via control gene identified 1 of 13 (8%) of DiGeorge syndrome patients at birth in our cohort. The majority of patients had TREC/KREC levels in the normal range.

Prdm1 functions in the mesoderm of the second heart field, where it interacts genetically with Tbx1, during outflow tract morphogenesis in the mouse embryo.

Congenital heart defects affect at least 0.8% of newborn children and are a major cause of lethality prior to birth. Malformations of the arterial pole are particularly frequent. The myocardium at the base of the pulmonary trunk and aorta and the arterial tree associated with these great arteries are derived from splanchnic mesoderm of the second heart field (SHF), an important source of cardiac progenitor cells. These cells are controlled by a gene regulatory network that includes Fgf8, Fgf10 and Tbx1. Prdm1 encodes a transcriptional repressor that we show is also expressed in the SHF. In mouse embryos, mutation of Prdm1 affects branchial arch development and leads to persistent truncus arteriosus (PTA), indicative of neural crest dysfunction. Using conditional mutants, we show that this is not due to a direct function of Prdm1 in neural crest cells. Mutation of Prdm1 in the SHF does not result in PTA, but leads to arterial pole defects, characterized by mis-alignment or reduction of the aorta and pulmonary trunk, and abnormalities in the arterial tree, defects that are preceded by a reduction in outflow tract size and loss of caudal pharyngeal arch arteries. These defects are associated with a reduction in proliferation of progenitor cells in the SHF. We have investigated genetic interactions with Fgf8 and Tbx1, and show that on a Tbx1 heterozygote background, conditional Prdm1 mutants have more pronounced arterial pole defects, now including PTA. Our results identify PRDM1 as a potential modifier of phenotypic severity in TBX1 haploinsufficient DiGeorge syndrome patients.

Adaptor protein Crk-like (CrkL) controls natural killer cell function via regulating the accumulation of activating receptors and phosphorylated Vav-1 molecules at immunological synapses (INM2P.433)

Abstract Very few studies have addressed how CrkL, a ubiquitous adaptor protein, regulates the immune response, especially in NK cells. Previous studies indicate that CrkL is required for NKG2D-mediated cellular cytotoxicity (NC) and CD16 signaling triggered antibody mediated cellular cytotoxicity (ADCC). However, how CrkL protein controls NK cell cytotoxicity remains unclear. Here we used lentiviral inducible shRNA to silence CrkL in human NK cell line and primary NK cells. Inducible knockdown of CrkL significantly reduced NK-target conjugation, degranulation, and cytotoxicity in both NC- and ADCC-mediated immune responses. Further investigation on the function and signaling transduction at the NK cytotoxic immunological synapse (IS) reveals that polarization of lytic granules, and accumulation of both F-actin and phosphorylated Vav-1 at the IS were greatly reduced in CrkL-silenced NK cells. NK cell activation involves in actin-dependent activating receptor clustering. CrkL silencing resulted in reduced accumulation of ligands for CD16 and NKG2D on the lipid bilayer. Similar results were obtained in NK cells from DiGeorge Syndrome patients (CrkL gene deletion). We thus propose a new model for adaptor protein CrkL function in NK cell activation: CrkL controls NK cell cytotoxicity via promoting F-actin accumulation and lytic granule polarization by modulating the accumulation of activating receptors and phosphorylated Vav-1 molecules at the IS.