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Overview of clinical outcome at last follow-up in 20 partial DiGeorge syndrome (pDGS) patients with 22q11·2 microdeletion (1995-2005).
Source publication
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 as...
Contexts in source publication
Context 1
... infectious and non-infectious complications occurred in both SR and HR groups (Table 3). At autopsy of patient 2, lymphoproliferative disease (LPD) with polyclonal T cell infiltrations of lymph nodes, liver, spleen, lungs and kidneys without skin or gut involvement was demonstrated. ...
Context 2
... developmental and cardiac outcomes are depicted in Table 3. All but two patients underwent at least one surgical cardiac intervention. ...
Context 3
... HR patients (patients 2, 6, 10 and 20) died for non- cardiac reasons: polyclonal LPD proven by autopsy; Stenotro- phomonas maltophilia pneumonia; Pseudomonas pneumonia/ sepsis; autoimmune neutropenia/thrombocytopenia, re- spiratory syncitial virus-bronchiolitis and P. cepacia pneu- monia. One HR patient (patient 14) and two SR patients (patients 12 and 16) died from cardiac causes only (Table 3). Four of seven patients with major aortopulmonary collateral arteries (MAPCA), pulmonary atresia (PA) and ventricle septum defect (VSD) died from non-cardiac causes (patients 2, 6, 10 and 14). ...
Context 4
... et al. reported on 10 of 30 pDGS patients with autoimmune symptoms with or without autoantibodies and showed associated low immunoglobulins or poor antibody responses after specific vaccination with protein and polysaccharide antigens [7]. All patients of our cohort with proven autoimmunity or LPD belonged to the HR group (Table 3); however, we were unable to detect relevant defi- ciencies of specific antibody responses to protein antigens in this group. We have no data on responses to polysaccha- ride vaccination. ...
Context 5
... novel observation within our series was the develop- ment of polyclonal LPD (patient 2; Table 3) with a clinical picture different from previously published LPDs described in cDGS patients [10,11]. Secondary T cell losses after post- interventional chylothorax, removal of residual thymic tissue by repetitive cardiac surgery or multiple infections with lym- photropic viruses (Table 3) may be contributing factors to explain the development of LPD in the presence of sufficient overall T cells; however, definitive answers remain elusive. ...
Context 6
... novel observation within our series was the develop- ment of polyclonal LPD (patient 2; Table 3) with a clinical picture different from previously published LPDs described in cDGS patients [10,11]. Secondary T cell losses after post- interventional chylothorax, removal of residual thymic tissue by repetitive cardiac surgery or multiple infections with lym- photropic viruses (Table 3) may be contributing factors to explain the development of LPD in the presence of sufficient overall T cells; however, definitive answers remain elusive. It is noteworthy that Kanaya et al. reported on one pDGS patient with microdeletion dying of haemophagocytic lym- phohistiocytosis at the age of 26 months, a complication that may resemble LPD if autopsy is not performed [29]. ...
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Citations
... Persistent low numbers of CD4 + CD45RA + and CD8 + T cells in DGS patients rendered them more prone to lethal infections and lymphoproliferative disorders during the follow-up period [ 47]. Feger U et al., 2006 de ned novel subsets of T cells expressing the immunomodulatory molecule HLA-G as CD4 HLA-GC distinct Treg cells [26]. ...
Aim
The study aimed to offer better genetic evaluation and consultation for DiGeorge syndrome (DGS) patients by combining screening of 22q11.2 and immunologic studies. A basic immune profile including the basic CD panel and immunoglobulins estimation was performed. TRECS and KRECS expression were studied in addition to measuring serum IL33, Obestatin, HLA-G, and Procalcitonin serum levels.
Methods
All investigations were performed for DGS patients (n = 33) and the matched control group (n = 45). Polymorphic 22q11.2 markers mapping was performed by PCR-STR technique. Lymphocyte subsets immunophenotyping was done using flow cytometry, while measurement of serum immunoglobulins was estimated using nephelometry. Real-time PCR was the method used for TRECs and KRECs measurement. Serum IL33, Obestatin, HLA-G, and Procalcitonin levels were determined using an Enzyme-linked immunosorbent assay (ELISA). Data was coded, tabulated, and statistically analyzed using SPSS version 19.0 software.
Results
In our case–control study, KREC expression was significantly elevated in DGS compared to healthy controls (P = 0.0008). There was also a significant increase in immunoglobulin levels in DGS. CD8% as well as CD8 absolute count in the patients with DGS were significantly lower than in the healthy control (P = 0.01273 and 0.05358 respectively). There were no significant differences in IL33, Obestatin, HLA-G, and Procalcitonin levels between DGS patients compared to the control group. Our results concerning the distinct segment of 22q11.2 as a DGS susceptibility region revealed an informative novel atypical interstitial homozygous deletion. This deletion included D22S944 and COMT absence, and D22S941 and D22S264 presence. Out of 33 DGS patients, three patients showed deletion in the D22S944 marker only in the presence of D22S941, and D22S264 markers. Therefore, we could assume that D22S944 is a common deleted marker in non-isolated DGS patients.
Conclusion
Combining 22q11.2 region screening, immune profile studies, and TRECS and KRECS expression offers a new comprehensive approach for DGS patients. This approach provides a better strategy for genetic consultation for DGS patients. Moreover, this study may be the first to show a small interstitial 22q11.2 deletion stereotype in a DGS patient and also showed that the smallest deletion at the 22q11.2 region is enough to confer the DGS phenotype.
... Age-related percentiles of CD4 + CD31 + CD45RA + expressing T-cell subsets were derived from a pediatric volunteer population comprising healthy children prior to elective surgical procedures in the University Children's Hospital Zürich, Switzerland [24][25][26]. ...
... Univariable and multivariable Weibull models were constructed and adjusted by the same confounders as described above. For this purpose, the measured CD4 + CD31 + CD45RA + T-cell counts were compared with the absolute numbers of calculated percentiles of a healthy pediatric population published in our center [24,25,31]. ...
... In order to develop age-specific percentiles for RTE, 74 healthy infants and children (51 males, 23 females, 0-18 years of age) were analyzed [24,25,31]. The cohort was divided in seven age groups (0 to 12 months, 1 to 4 years, 4 to 6 years, 6 to 9 years, 9 to 12 years, 12 to 15 years, and 15 to 18 years). ...
After allogeneic hematopoietic stem cell transplantation (allo-HSCT), the recurrence of recent thymic emigrants (RTE) and self-tolerant T cells indicate normalized thymic function. From 2008 to 2019, we retrospectively analyzed the RTE-reconstitution rate and the minimal time to reach normal age-specific first percentiles for CD31⁺CD45RA⁺CD4⁺T cells in 199 pediatric patients after allo-HSCT for various malignant and non-malignant diseases. The impact of clinically significant graft-versus-host disease (GvHD), age at transplantation, underlying disease and cumulative area under the curve of busulfan on RTE-reemergence was assessed in multivariable longitudinal analysis. RTE-reconstitution (coefficient −0.24, 95% CI −0.33 to −0.14, p < 0.001) was slowed down by GvHD and the time to reach P1 was significantly longer (Event Time Ratio 1.49, 95% CI 1.25 to 1.78, p < 0.001). Older age at transplantation was also associated with a slower RTE-reconstitution (coefficient −0.028, 95% CI −0.04 to −0.02, p < 0.001) and time to reach P1 was significantly longer (Event Time Ratio 1.03, 95% CI 1.02 to 1.05, p < 0.001). RTE-reconstitution velocity was not influenced by underlying disease or cumulative busulfan exposure. In summary, duration until thymic reactivation was independent of both conditioning intensity and underlying disease and was negatively influenced by older age and GvHD.
... The lower normal cut-off values for the naive CD4 + T cells and CD8 + T cells were accepted as 430 and 490 cells/µL, respectively. 13 The HR patients have more documented lethal infections and lymphoproliferative complications. 13 In our cohort, during the last clinical examination of the study, six patients were classified as HR (patients 2, 3, 6, 8, 12, 13), while the rest as SR (patients 1,4,5,7,9,10,11,14,15,17,18) (Table 1). ...
... 13 The HR patients have more documented lethal infections and lymphoproliferative complications. 13 In our cohort, during the last clinical examination of the study, six patients were classified as HR (patients 2, 3, 6, 8, 12, 13), while the rest as SR (patients 1,4,5,7,9,10,11,14,15,17,18) (Table 1). Patient 16 was excluded from the evaluation due to the loss of follow-up. ...
... Abbreviations: CSB, Class-switched B cells; IQR, interquartile range; n.s., non-significant; SD, standard deviation. *Mann-Whitney U test.Eberle et al13 showed CD4 + CD45RA + CD31 + T cells as a useful marker for early detection of persistent impaired thymic activity in DGS patients. In line with Eberle et al study, our patients with reduced IgM showed lower numbers of naive CD4 + and RTE T cells compared to the patients with normal IgM levels. ...
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+ and CD8+T cells counts and percentages of switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism was 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. This article is protected by copyright. All rights reserved.
... [5][6][7][8] About 60% of the patients may experience recurrent infections manifesting as sinusitis, otitis media (OME), bronchitis, and pneumonia, 9 and these are secondary not only to the immunologic dysfunction but also to the anatomic abnormalities that often accompany the syndrome. 2,7,10,11 Autoimmune and allergic manifestations are also frequently seen in DGS patients. 9,[12][13][14] Given the great variability of the clinical and immunological manifestations and that these patients are often followed by different specialists, it has been difficult to determine the contribution of each of these factors to the final phenotype. ...
... The results of the multivariate analysis showed that the increased susceptibility to URTI and OME are related to the underlying anatomical defects (GERD or functional and anatomical palatal alterations) and to nonprotective pneumococcal antibody titer. 2,7,10,11 The frequency of URTI was also increased in patients with asthma/rhinitis, as also observed in the general population. 30 Antibiotic prophylaxis was recommended ...
DiGeorge syndrome (DGS) is a primary immunodeficiency characterized by various degrees of T-cell deficiency. In partial DGS (pDGS), other risk factors could predispose to recurrent infections, autoimmunity and allergy. The aim of this study was to assess the impact of different factors in the development of infections, autoimmunity and/or allergy in patients with pDGS. We studied 467 pDGS patients in follow-up at Great Ormond Street Hospital. Using a multivariate approach, we observed that palatal anomalies represent a risk factor for the development of recurrent otitis media with effusion. Gastroesophageal reflux/dysphagia and asthma/rhinitis represent a risk factor for the development of recurrent upper respiratory tract infections. Allergy and autoimmunity were associated with persistently low IgM levels and lymphopenia, respectively. Patients with autoimmunity showed lower levels of CD3+, CD3+CD4+ and naïve CD4+CD45RA+CD27+ T-lymphocytes as compared with pDGS patients without autoimmunity. We also observed that the physiological age-related decline of the T-cell number was slower in pDGS patients as compared with age-matched controls. The age-related recovery of the T-cell number depended on a homeostatic peripheral proliferation of T-cells, as suggested by an accelerated decline of the naïve T-lymphocytes in pDGS as well as a more skewed T-cell repertoire in older pDGS patients. These evidences suggest that premature CD4+ T-cell aging and lymphopenia induced spontaneous peripheral T-cell proliferation might contribute to the pathogenesis of autoimmunity in patients with pDGS. Infections in these patients represent, in most of the cases, a complication of anatomical or gastroenterological anomalies rather than a feature of the underlying immunodeficiency.
... As expected, TREC circles and recent thymic immigrants defined by CD31 are decreased in most patients with 22q11.2del. [114][115][116] The two markers are not completely binary. TREC counts decline with age within the CD31 + recent thymic immigrant population suggesting that proliferation within the compartment occurs. ...
Chromosome 22q11.2 deletion syndrome is the most common microdeletion syndrome in humans. The effects are protean and highly variable, making a unified approach difficult. Nevertheless, commonalities have been identified and white papers with recommended evaluations and anticipatory guidance have been published. This review will cover the immune system in detail and discuss both the primary features and the secondary features related to thymic hypoplasia. A brief discussion of the other organ system involvement will be provided for context. The immune system, percolating throughout the body can impact the function of other organs through allergy or autoimmune disease affecting organs in deleterious manners. Our work has shown that the primary effect of thymic hypoplasia is to restrict T cell production. Subsequent homeostatic proliferation and perhaps other factors drive a Th2 polarization, most obvious in adulthood. This contributes to atopic risk in this population. Thymic hypoplasia also contributes to low regulatory T cells and this may be part of the overall increased risk of autoimmunity. Collectively, the effects are complex and often age‐dependent. Future goals of improving thymic function or augmenting thymic volume may offer a direct intervention to ameliorate infections, atopy, and autoimmunity.
... The majority of DGS patients present with Tlymphocyte immunodeficiency (Eberle et al., 2009;McLean-Tooke et al., 2008). The decreased T-lymphocyte count is a result of hypoplasia of the thymus, the site of T cell maturation and development. ...
... A minority of DGS patients are athymic, but the majority have a hypoplastic thymus with normal or moderately decreased T-cell counts (McLean-Tooke et al., 2008;Patel et al., 2012). Over time, cluster of differentiation (CD) 3, CD4, and CD8 T-cell counts continually decline, which results in impaired immune function (Eberle et al., 2009;McLean-Tooke et al., 2008;Patel et al., 2012). It is possible that thymus abnormalities are due to dysregulation of receptor tyrosine kinase signaling. ...
DiGeorge syndrome (DGS) is one of the most common genetic syndromes, resulting from random mutations in the 22q11.2 region of chromosome 22. The effects of DGS are highly variable and include craniofacial abnormalities, cardiac defects, immune deficiencies, cognitive impairment and psychiatric disorders. The molecular mechanisms underlying the manifestations of DGS are not completely understood. Identifying specific mutations and molecular pathways involved in DGS and the resulting phenotypic characteristics are areas of ongoing investigation. Many of the manifestations of DGS have been linked to deletion of the T-box transcription factor 1 (TBX1) gene, which plays a role in neural crest cell migration, pharyngeal arch (PA) development and formation of the pharyngeal pouches. TBX1 interacts with many molecular pathways leading to craniofacial defects and aberrant neural crest cell migration and survival. Many of the psychiatric and cognitive effects of DGS have been linked to mutations in genes ...
... Other authors have observed an increased risk of severe infections and autoimmune and lymphoproliferative complications in a specific immunologic subgroup of infants with 22q11DS. 39 Specific studies are needed to identify immunologic markers predictive of a higher risk for severe infections and autoimmune manifestations in patients with 22q11DS. ...
... As a consequence of the thymic dysfunction, and subsequent impaired thymocyte development, individuals bearing this deletion show T-lymphocyte and humoral deficiencies together with other immune defects that are not related to other phenotypic features. [2][3][4][5] When adulthood is reached, T-lymphocyte numbers of these patients are normal, but alterations such as shorter telomere length of the naive subset, oligoclonal T-lymphocyte expansions, 4 and altered T-cell differentiation 6 are present, pointing to deregulated peripheral homeostasis. Even if some of the patients diagnosed with the 22q11.2 ...
... Normal or near normal T-cell numbers can be found even in those with an apparently absent or hypoplastic thymus and in these it is probable that some thymic tissue is ectopically placed (57). There may be a small subset of more severely deficient 22q.11 -pDGS patients with T-cell numbers near the lower end of the range who have an increased susceptibility to "T-cell" type pathogens such as Candida albicans and viral infections and an increased non-cardiac mortality (58,59). Hypocalcemia was an associated feature of this subgroup in one of these studies (58) and was also associated with lymphopenia in another study of CHARGE patients (51). ...
... Their infections tend to be of a sinopulmonary nature, more consistent with a humoral than a T-cell immunodeficiency. Susceptibly to such respiratory tract infections is likely to be at least partly due to non-immunological issues such as velo-pharyngeal insufficiency, eustachian tube dysfunction, disco-ordinate swallowing, gastro-esophageal reflux, and sometimes tracheo-bronchomalacia (59,61). ...
The commonest association of thymic stromal deficiency resulting in T-cell immunodeficiency is the DiGeorge syndrome (DGS). This results from abnormal development of the third and fourth pharyngeal arches and is most commonly associated with a microdeletion at chromosome 22q11 though other genetic and non-genetic causes have been described. The immunological competence of affected individuals is highly variable, ranging from normal to a severe combined immunodeficiency when there is complete athymia. In the most severe group, correction of the immunodeficiency can be achieved using thymus allografts which can support thymopoiesis even in the absence of donor-recipient matching at the major histocompatibility loci. This review focuses on the causes of DGS, the immunological features of the disorder, and the approaches to correction of the immunodeficiency including the use of thymus transplantation.
... However, recently it has been shown in patients with 22q11.2 deletion syndrome that there is an increase in non-cardiac mortality with T-cell counts less than the 10th percentile for age, with four of 11 children succumbing to infections or Epstein-Barr virus associated lymphoproliferative disease [11]. However, the clinical consequences of T-cell lymphopenia in 22q11.2 ...
Severe combined immunodeficiency is a life-threatening primary immune deficiency characterized by low numbers of naïve T cells. Early diagnosis and treatment of this disease decreases mortality. In 2008, Wisconsin began newborn screening of infants for severe combined immunodeficiency and other forms of T-cell lymphopenia by the T-cell receptor excision circle assay. In total, 207,696 infants were screened. Seventy-two infants had an abnormal assay. T-cell numbers were normal in 38 infants, abnormal in 33 infants, and not performed in one infant, giving a positive predictive value for T-cell lymphopenia of any cause of 45.83% and a specificity of 99.98%. Five infants with severe combined immunodeficiency/severe T-cell lymphopenia requiring hematopoietic stem cell transplantation or other therapy were detected. In summary, the T-cell receptor excision circle assay is a sensitive and specific test to identify infants with severe combined immunodeficiency and severe T-cell lymphopenia that leads to life-saving therapies such as hematopoietic stem cell transplantation prior to the acquisition of severe infections.
