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Background Individuals with 22q11.2 deletion syndrome (22q11.2DS) are at risk for having both psychotic and immune disorders, thus, implying a possible link between the two. The aim of the current study was to evaluate the usefulness of the neutrophiles to leukocytes ratio (NLR), an inflammatory marker, as a bio-marker for overt and prodromal psychotic symptoms in 22q11.2DS. Methods Forty-nine individuals with 22q11.2DS (13 with psychotic disorders and 36 without psychotic disorders) and 30 age- and sex-matched healthy controls underwent psychiatric evaluation using a structured psychiatric interview, the Scale of Prodromal Symptoms (SOPS) and the Global Assessment of Functioning (GAF) scale. Blood samples were collected from all participants on the day of assessment. NLR was calculated, compared among the study groups and correlated with SOPS and GAF scores. The non-psychotic 22q11.2DS group was further divided into high- and low-inflammation groups by NLR values and the analyses were done again. Results NLR was higher in the psychotic- and the high-inflammation non-psychotic 22q11.2DS groups compared to the low-inflammation non-psychotic 22q11.2DS group and controls. In the high-inflammation non-psychotic 22q11.2DS group NLR increase was associated with an increase of total negative symptoms scores on SOPS and a decrease in GAF scores. Conclusion Our results suggest the potential utility of NLR as a bio-marker for psychotic disorders and subthreshold prodromal symptoms in 22q11.2DS. Furthermore, they imply that a disequilibrium between the innate and adaptive arms of the immune system facilitates the progression of psychosis in at risk populations. Further longitudinal studies are warranted to validate our findings, as this was a cross sectional observation.

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

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. The congenital disorder 22q11.2 deletion syndrome (22qDS), characterized by a hemizygous deletion of 1.5-3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder (estimated prevalence of 1 in 4000) and the second risk factor for schizophrenia. Nine of - 30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism (COMT, UFD1L, DGCR8, MRPL40, PRODH, SLC25A1, TXNRD2, T10, and ZDHHC8). Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neuronal metabolism or synaptic signaling, partly explaining the higher incidence in developmental and behavioral deficits in these individuals. Here, we investigated whether mitochondrial outcomes and metabolites from 22qDS children segregated with the altered dosage of one or several of these mitochondrial genes contributing to 22qDS etiology and/or morbidity. Plasma metabolomics, lymphocytic mitochondrial outcomes, and epigenetics (histone H3 Lys-4 trimethylation and 5-methylcytosine) were evaluated in samples from 11 22qDS children and 13 age- and sex-matched neurotypically developing controls. Metabolite differences between 22qDS children and controls reflected a shift from oxidative phosphorylation to glycolysis (higher lactate/pyruvate ratios) accompanied by an increase in reductive carboxylation of α-ketoglutarate (increased concentrations of 2-hydroxyglutaric acid, cholesterol, and fatty acids). Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1α, MYC, and metabolite controls. This comprehensive profiling served to clarify the biochemistry of this disease underlying its broad, complex phenotype.

Background Recurrent sinopulmonary infections are common in children with CHARGE (Coloboma, Heart disease, choanal Atresia, growth/mental Retardation, Genitourinary malformations, Ear abnormalities) syndrome, but no prospective studies on immune function have been conducted. Objective This study aims to examine and compare the immune phenotype of patients with CHARGE syndrome to those with 22q11.2 deletion and healthy controls. Methods A total of 21 patients attended a multidisciplinary CHARGE clinic. All patients had CHD7 mutational analysis performed. Patients with CHARGE syndrome had lymphocyte subsets, immunoglobulins (IgG, A, M), functional protein, and polysaccharide vaccine responses measured at initial evaluation. A total of 55 healthy controls were prospectively recruited, whereas 40 patients with 22q11.2 deletion were retrospectively identified through medical records. A separate analysis compared serial lymphocyte counts and ionized calcium levels between patients with CHARGE syndrome and those with 22q11.2 deletion in the first 72 months of life. Results Despite recurrent childhood ear and chest infections, only 2 children with CHARGE syndrome had an identifiable immune defect (reduced serum IgA). In contrast, T-cell lymphopenia, low immunoglobulin levels, and specific antibody deficiency were noted in patients with 22q11.2 deletion. A greater proportion of patients with 22q11.2 deletion had persistent lymphopenia (57% vs 30%) and hypocalcemia (60% vs 37.5%) compared with patients with CHARGE syndrome in the first 72 months of life. Conclusions Although phenotypic overlap exists between CHARGE and 22q11.2 deletion syndromes, no significant immune defects were detected in this cohort of patients with CHARGE syndrome at the time of testing. Lymphopenia and hypocalcemia occur in both conditions early in life, but is more pronounced in patients with 22q11.2 deletion.

Interstitial telomeric sequences (ITSs), telomere-like repeats at intrachromosomal sites, are common in mammals and consist of tandem repeats of the canonical telomeric repeat, TTAGGG, or a repeat similar to this. We report that the ITS in human chromosome region 22q11.2 is, in the sequenced genome database, 101 tandem repeats of the sequence TTAGGGAGG. Using the primed in situ labeling (PRINS) technique and primers against the canonical telomeric repeat (TTAGGG), we illuminated telomeric sites for all chromosomes and an ITS locus at 22q11.2. Using the TTAGGGAGG sequence, we designed PRINS primers that efficiently and specifically illuminate the 22q11.2 ITS locus without illuminating telomeric and other ITS loci. The 22q11.2 locus has more repeat units than other ITSs loci enabling an unprecedented high detection frequency for this interstitial telomere locus. The 22q11.2 is associated with hot spots for disease-related chromosome breaks for multiple disorders, such as DiGeorge syndrome and chronic myeloid leukemia. We describe our findings that the ITS at 22q11.2 is in the same area of, and proximal to the common rearrangement region of multiple disorders. We suggest that the ITS might be involved in DNA repair processes in this area to protect the chromosome from more serious damage.

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. Methods TREC/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. Results All 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

Background22q11.2 microdeletion is the most common microdeletion in the global population. Congenital cardiac disease is the most frequently observed feature of this syndrome. The prognosis of patients with 22q11.2 copy number aberrations varies from those without 22q11.2 deletion or duplication.MethodsWe enrolled 241 patients from Nanjing Drum Tower Hospital and Nanjing Sick Children’s Hospital, 227 being scheduled for cardiac surgery, and 14 cases being fetuses aged from 24 to 36 gestational weeks. We performed karyotypic analysis and multiplex ligation-dependent probe amplification in all cases.ResultsKaryotypic analysis demonstrated 3 cases with trisomy 21, and 1 case with mosaic trisomy 8 [47,XY,+8/46,XY(1:2)]. Multiplex ligation-dependent probe amplification analysis revealed 10 cases (4.15%) with changes in the number of copies within the region of 22q11.2, of which 7 cases were hemizygous interstitial microdeletion from CLTCL1 to LZTR1, 1 case with deletion of the region from CLTCL1 to PCQAP, and 2 cases with 22q11.2 duplication, one of which spanned from ZNF74 to LZTR1, and simultaneously showed trisomy 21 by karyotyping analysis, and the other spanned from HIC2 to TOP3B. The phenotypes of the cardiac lesions included 3 cases of ventricular septal defect, 3 of tetralogy of Fallot, 2 of combined ventricular and atrial septal defects, and 2 with pulmonary arterial stenosis.ConclusionsPatients with congenitally malformed hearts who are scheduled for cardiac surgery, as well as fetuses with congenital cardiac disease, should routinely undergo karyotypic analysis and examination for 22q11.2 aberrations. Multiplex ligation-dependent probe amplification has been proven to be a cost-effective diagnostic technique for 22q11 deletion syndrome.

In the present report we have studied the expression of a lymphocyte homing receptor, the CD44 antigen, and of HECA-452, a high endothelial-specific antigen, during the development of the human immune system. We found that prothymocyte immigrants of the thymus already expressed the CD44 antigen. Similarly, the first peripheral T lymphocytes in fetal lymph nodes, tonsils and gut-associated lymphoid tissue were also CD44+. Cortical thymocytes and germinal center cells were CD44-. CD44 antigen expression was, thus, not limited to mature recirculating lymphocytes. This suggests that CD44 may not only be involved in recirculation of mature lymphocytes but also in the migration of prothymocytes to their site of maturation, i.e. the thymus. High endothelial venules (HEV) were not demonstrable at the early onset of lymphocyte immigration into the developing lymphoid organs. However, when large-scale influx of lymphocytes occurred, it paralleled HEV development. HECA-452 antigen expression preceded the morphological transformation of endothelium into a HEV phenotype. Expression of this antigen therefore, independently reflected the specialized nature of high endothelium. In a patient with complete DiGeorge's syndrome normal HEV developed, indicating that the presence of T lymphocytes is not a requirement for HEV development. Interestingly, a subpopulation of venules located in the thymic medulla near the cortico-medullary junction expressed the HECA-452 antigen. These vessels, which had flat or intermediately high endothelium, are probably involved in lymphocyte migration to the thymus.

DiGeorge and Velocardiofacial syndromes (DGS/VCFS) are endowed by a similar complex phenotype including cardiovascular, craniofacial, and thymic malformations, and are associated with heterozygous deletions of 22q11 chromosomal band. The Typically Deleted Region in the 22q11.21 subband (here called TDR22) is very gene-dense, and the extent of the deletion has been defined precisely in several studies. However, to date there is no evidence for a mechanism of haploinsufficiency that can fully explain the DGS/VCFS phenotype. In this study, we show that the candidate gene HIRA/Tuple1 mapping on the non-deleted TDR22, in DGS/VCFS subjects presents a delayed replication timing. Moreover, we observed an increase in the cell ratio showing the HIRA/Tuple1 locus localised toward the nuclear periphery. It is known that replication timing and nuclear location are generally correlated to the transcription activity of the relative DNA region. We propose that the alteration in the replication/nuclear location pattern of the non-deleted TDR22 indicates an altered gene regulation hence an altered transcritpion in DGS/VCFS. © 2004 Elsevier B.V. All rights reserved.

Low copy repeats (LCRs) located in 22q11.2, especially LCR-B, are susceptible to rearrangements associated with several relatively common constitutional disorders. These include DiGeorge syndrome, Velocardiofacial syndrome, Cat-eye syndrome and recurrent translocations of 22q11 including the constitutional t(11;22) and t(17;22). The presence of palindromic AT-rich repeats (PATRRs) within LCR-B of 22q11.2, as well as within the 11q23 and 17q11 regions, has suggested a palindrome-mediated, stem-loop mechanism for the generation of such recurring constitutional 22q11.2 translocations. The mechanism responsible for non-recurrent 22q11.2 rearrangements is presently unknown due to the extensive effort required for breakpoint cloning. Thus, we have developed a novel fluorescence in-situ hybridization and primed in-situ hybridization (PRINS) approach and rapidly localized the breakpoint of a non-recurrent 22q11.2 translocation, a t(4;22). Multiple primer pairs were designed from the sequence of a 200 kb, chromosome 4, breakpoint-spanning BAC to generate PRINS probes. Amplification of adjacent primer pairs, labeled in two colors, allowed us to narrow the 4q35.1 breakpoint to a 6.7 kb clonable region. Application of our improved PRINS protocol facilitated fine-mapping the translocation breakpoints within 4q35.1 and 22q11.2, and permitted rapid cloning and analysis of translocation junction fragments. To confirm the PRINS localization results, PCR mapping of t(4;22) somatic cell hybrid DNA was employed. Analysis of the breakpoints demonstrates the presence of a 554 bp palindromic sequence at the chromosome 4 breakpoint and a 22q11.2 location within the same PATRR as the recurrent t(11;22) and t(17;22). The sequence of this breakpoint further suggests that a stem-loop secondary structure mechanism is responsible for the formation of other, non-recurrent translocations involving LCR-B of 22q11.2.

During the last few years, various technologies and applications of fluorescence in situ hybridization (FISH) have been developed. Hybridization on nuclei allows an increase in the resolution of the technique. It also permits the characterization of some chromosomal abnormalities such as trisomies, monosomies or translocations in pathological cells when it is difficult to obtain metaphases. Recently, several methods which extend the chromatin or the DNA molecules have been developed. Such a support increases the FISH resolution to the molecular level.

The velocardiofacial syndrome is an autosomal dominant disorder characterized by cleft palate, cardiac anomalies, characteristic facies, and learning disabilities. The Di George anomaly involves developmental defects of the third and fourth pharyngeal pouches, resulting in thymic and parathyroid hypoplasia and cardiac defects. The cases of individuals in two families help substantiate the notion that the Di George anomaly occurs as a feature of the velocardiofacial syndrome. The proband in family 1 was a male infant with persistent hypocalcemia and cardiac defects consisting of truncus arteriosus, atrial septal defect, ventricular septal defect, and abnormal aortic arch vessels. Autopsy revealed absence of thymic and parathyroid tissue, and the Di George anomaly was diagnosed. His father had a submucous cleft palate, T cell dysfunction, and facial features consistent with the velocardiofacial syndrome. This is the third case of male-to-male transmission of velocardiofacial syndrome. The proband of family 2 was a 4-year-old girl with developmental delay, persistent neonatal hypocalcemia, ventricular septal defect, T cell dysfunction, and facial features of the velocardiofacial syndrome. The Di George anomaly has been reported to occur in at least 18 different disorders. The observation that the Di George anomaly is a component manifestation of the velocardiofacial syndrome in these two families provides further evidence that the Di George anomaly is not a distinct syndrome of a single origin but rather a heterogeneous developmental field defect. It is proposed that all previously reported cases of autosomal dominant Di George anomaly are examples of the velocardiofacial syndrome.

Premortem diagnosis of the DiGeorge syndrome and its partial variants relies on the demonstration of a primary defect in cell-mediated immunity, generally in the setting of an infant with congenital heart disease, hypocalcemia, absence of a thymic shadow, and typical dysmorphic features. Although T-cell enumeration is considered a vital part of the diagnostic evaluation, no studies to date have addressed the issue of appropriate reference data in infants with congenital heart disease. We therefore undertook a prospective descriptive study of lymphocyte phenotype analysis in 27 nontransfused infants undergoing diagnostic cardiac catheterization. Striking differences were seen between patients and adult controls in means percentages and numbers of most lymphocyte subsets analyzed. Few differences were found in comparing the patient data to values for age-matched control infants without heart disease. The data are discussed with reference to published values for patients with partial DiGeorge syndrome. It is concluded that lymphocyte phenotype analysis in the diagnostic evaluation of patients with suspected DiGeorge syndrome must utilize appropriate reference values.

Several clinical observations suggest the presence of cellular abnormalities in patients with elevated serum IgE levels. Patients with atopic dermatitis are prbne to unusually severe skin infections with herpes simplex and vaccinia’.’ and have an increased susceptibility to molluscum contagiosum’ and warts.4 These clinical observations are correlated with the observation that patients with atopic dermatitis also have impaired in vivo delayed-type hypersensitivity responses to intradermal skin testing using common recall antigens,5. ’ and a reduced rate of contact sensitivity to Rhus antigen.‘. * The syndrome of hyperimmunoglobulinemia E, recurrent staphylococcal infections, and chronic dermatitisq is frequently complicated by candidiasis and by severe herpes simplex infections. The latter syndrome is also associated with absent in vivo delayed hypersensitivity responses to common microbial antigens and reduced in vitro lymphocyte proliferative responses to alloantigens or soluble antigens such as tetanus toxoid or Monilin. Finally, it is also well known that patients with primary T cell immunodeficiency disorders, such as DiGeorge syndrome, Wiskott-Aldrich syndrome, or Nezelof syndrome, often have elevated serum IgE levels.‘“-” Taken together, these observations suggest a close relationship between cellular abnormalities and allergic diseases associated with elevated IgE levels. This review explores some of these relationships. Potential cellular interactions are reviewed in Fig. 1.

A female infant with DiGeorge syndrome associated with severe T-cell immunodeficiency underwent a successful bone marrow transplantation from her HLA-identical, mixed leukocyte culture-nonreactive brother at 5 months of age. Mature circulating T cells and mitogen-induced proliferative responses were detectable at 10 days posttransplant, and by 8 months post-transplant functional T- and B-cell reconstitution was documented by normal responses to mitogens and normal levels of serum immunoglobulins as well as in vitro and in vivo T-cell reactivity to specific antigens and production of specific antibody to T cell-dependent antigens in vivo. Phytohemagglutinin-induced interleukin-2 production and cell surface interleukin-2 receptor expression improved posttransplant, with normal production values observed by 8 months posttransplant. Histologic examination of appendix and thoracic lymph node obtained 9 and 17 months posttransplant, respectively, revealed near-normal lymphoid architecture, with germinal center formation providing morphologic confirmation of reconstitution. Stable split lymphoid chimerism with T cells of donor origin and B cells remaining recipient in origin was documented by sex chromosome analysis. Two years posttransplant the subject remains free of serious infections. In conclusion, this case indicates that bone marrow transplantation can produce peripheral immunoreconstitution without need for significant thymic influence, most likely by providing a source of postthymic T cells, and that bone marrow transplantation should be considered a therapeutic option in patients with DiGeorge syndrome associated with severe T-cell deficiency.

Mucosal mast cells have been examined in the small intestinal mucosae of nude mice and nude rats, B rats and a child with the DiGeorge syndrome. In all three species, mast cells were present in normal numbers despite the athymic status of the nude mice and nude rats, the vestigial nature of the thymus in the child, and the functionally T lymphocyte-deprived status of the B rats. Connective tissue mast cells were also plentiful in skins and tongues of the nude mice and the child with thymic aplasia. It is concluded that normally neither population of mast cells has a obligatory dependence on the thymus or T lymphocytes for its differentiation, but that mucosal mast cells, under certain conditions of rapid hyperplasia, require an inductive influence provided by T lymphocytes.

This report concerns a baby with the features of Di George syndrome. Bovine thymic extracts prepared in this laboratory were used to treat the baby between the ages of 1 and 18 months. A favourable evolution of the illness was noticed, suggesting the diagnosis of Di George syndrome in its partial form and/or a favourable response to the treatment with thymic extracts. The number of E-rosette forming T-lymphocytes in blood remained low during the 3.5 yr of the observation. The in vitro response of peripheral blood lymphocytes to phytohemagglutinin and to allogenic cells slowly increased during this period of time. Surprisingly, no change in the proportions of lymphocytes of high electrophoretic mobility and low electrophoretic mobility was observed, in contrast to the gradual change usually observed in normal individual age-matched controls.

Lymphotoxin (LT) production and [3H]thymidine incorporation by lymphocytes stimulated with phytohemagglutinin (PHA) were studied in 40 children with primary immune deficiency. LT activity was null in lymphocyte supernatants of children with severe combined immune deficiency (SCID). It was often diminished in culture supernatants from children with various other forms of immune deficiencies including common variable hypogammaglobulinemia and Bruton disease. Following thymus or bonemarrow grafting, the capacity to produce LT appeared in SCID but rose more slowly than the proliferative response to mitogens. This together with the observation that LT activity and [3H]thymidine uptake were dissociated in several cases, suggested that these two functions of cell-mediated immunity might be attributable to different T-cell subsets.

The diagnostic evaluation of infants with suspected DiGeorge syndrome includes peripheral blood lymphocyte phenotype analysis by flow cytometry. Mononuclear cells are typically concentrated from infants' blood samples by Ficoll-Hypaque (FH) density gradient centrifugation prior to monoclonal antibody (Mab) staining. Having observed that lymphocyte percentages in samples prepared by this technique were low more often than anticipated based on the prevalence of the suspected diagnosis, we undertook a prospective study of 55 infants with congenital heart disease comparing FH with a whole-blood (WB) technique. Sixty healthy adult controls were similarly studied. We report the observation that FH-prepared mononuclear cells from blood samples of infants less than 4 months of age yield substantially different phenotypes than WB-prepared samples. The differences are related to red blood cell (RBC) contamination. No such difference was seen with adult samples. Unlike FH-prepared adult samples, contaminating RBCs are indistinguishable from lymphocytes through at least 4 months of age when assessed by the standard cytometric gating parameters of forward and 90 degrees light scatter. The use of a WB ammonium chloride lysis technique is recommended as most appropriate for the preparation of infants' blood samples.

• Results of studies on two male infants with incomplete expression of the DiGeorge syndrome are analyzed. Both infants demonstrated neonatal tetany with hypoparathyroidism, cardiovascular anomalies, and absence of a thymus shadow on roentgenographic examination. Some degree of cellular immunity was present in both infants, however, including normal in vitro responses to phytohemagglutinin, thus postponing attempts at thymus transplantation. Both infants died suddenly at home, one at age 7½ weeks and the other at age 44 weeks. At autopsy, no thymus was found in one, and a 2 × 2-mm thymus was detected after extensive search in the other. These cases emphasize the need for repeated monitoring of all immunologic measurements in the partial DiGeorge syndrome, so that early therapeutic intervention can be undertaken. (Am J Dis Child130:316-319, 1976)