DiGeorge syndrome is associated with a T-lymphocyte immunodeficiency. The prevalence of hypogammaglobu- linemia has not been reported. We found that. Abstract Chromosome 22q deletion syndrome, or DiGeorge syndrome, or velocardiofacial syndrome, is one of the most common multiple. DiGeorge syndrome (DS) is a rare congenital immunodeficiency disorder characterized Download as PDF Reviews of DiGeorge syndrome in the s described a diverse collection of phenotypic . Sign in to download full- size image.
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DiGeorge syndrome or 22q deletion syndrome is one of the most common genetic microdeletion syndromes in humans. In addition to physical manifestations, DiGeorge syndrome is associated with a high prevalence of psychiatric disorders, such as intellectual disability. PDF | The DiGeorge Syndrome was first described in as a primary immunodeficiency resulting from the abnormal development of the third. INTRODUCTION: The DiGeorge Syndrome was first described in as a primary immunodeficiency resulting KEYWORDS: DiGeorge syndrome; Immunologic deficiency syndromes; Thymus; 22q deletion. .. [Epub ahead of print].
It further contains probes for the detection of copy number status on 4q, 8p, 9q, 10p, 17p, and 22q13 regions as a cause of DiGeorge syndrome DGS , DGS type II or disorders with phenotypic features of DGS, associated with these regions. This assay is suitable for initial detection of deletions or duplications of above-mentioned regions or for confirmation of results obtained with a different MLPA assay. It should be used with human DNA derived from peripheral blood, buccal swab, un cultured amniotic fluid obtained in week 16 of the pregnancy or later and free from blood contamination, un cultured chorionic villi free from maternal contamination, or fetal blood. Copy number changes detected by only a single probe always require validation by another method. This assay is not intended to be used as standalone assay for clinical decisions. The results of this test should be interpreted by a clinical molecular geneticist or equivalent. Please note that this probemix is for In Vitro Diagnostic use IVD in the countries specified at the end of this product description.
This assay is not intended to be used as standalone assay for clinical decisions. The results of this test should be interpreted by a clinical molecular geneticist or equivalent. Please note that this probemix is for In Vitro Diagnostic use IVD in the countries specified at the end of this product description.
The overall birth prevalence of 22q According to GeneReview for 22q Cat eye syndrome CES has a large phenotypic variability, ranging from near normal to severe malformations.
The eyes are predominately affected.
CES is caused by the presence of an extra 22q The high frequency of 22q The extent of the 22q In this P DiGeorge probemix, 14 probes are located in this repeat region, see Table 2. This deletion includes the TBX1 gene. However, hemizygous Crkl loss is not associated with an abnormal clinical phenotype suggesting a gene dosing effect. The effect of compound heterozygosity for Tbx1 and Crkl deletions, on development of DGS features, is additive The function of TBX1 is complex and mediated through regulation of downstream transcription factors.
The detailed role of TBX1 in 22q. A much rarer but well characterized genetic association with a DGS phenotype occurs with interstitial deletions at chromosome 10p 30 — This has been designated DGS 2.
The clinical phenotype overlaps with that associated with 22q. Sensorineural hearing loss and mental retardation are relatively common features in those with 10p deletions but rare in 22q11 deletion cases; renal anomalies, and general growth retardation are more prevalent in 10p deletion than in 22q11 deletion cases Deletions at 10p syndrome have been estimated as having an incidence of 1 in ,, some 50 times less common than 22q.
The role of the genes deleted and responsible for the clinical picture is less well understood than in 22q deletion DGS but on-going work has identified some critical regions involved in developmental abnormalities 32 , A DGS phenotype including complete athymia may be part of this syndrome but there is marked variability in expression of the multiple clinical features.
The incidence has been estimated at 1 in CHD7 acts as a regulator of transcription of other genes. Its expression has been demonstrated in the NCC of the pharyngeal arches. Normal development of these structures has been shown to be dependent on the co-expression of Chd7 and Tbx1 in mice suggesting the likely mechanism by which CHARGE syndrome can lead to a DGS phenotype 39 , Retinoic acid affects Tbx1 expression in avian embryos 42 whilst it has also been shown that Tbx1 can, in at least some circumstances, regulate retinoic acid metabolism Fetal alcohol syndrome 44 — 46 and maternal diabetes 47 , 48 have also been associated with the DGS phenotype.
In the latter, there is often an associated renal agenesis.
It has been postulated that maternal diabetes can lead to interference with neural crest and mesenchymal cell migration In a large series of patients with 22q11 deletions, the proportion of affected individuals falling into the cDGS category was around 1. A much higher proportion had minor laboratory abnormalities suggesting pDGS.
Less is known of the frequency of severe immunodeficiency in 10p deletion DGS. However none of these patients were reported as having significant infections, suggesting that the immunodeficiency was likely partial rather than complete The proportion of cases affected with immunodeficiency is not well established as there is no reported large series looking at immunological parameters. Immunodeficiency may not always be considered in CHARGE; one recent report of a large series of cases did not provide any information on the prevalence of recurrent infections or immunodeficiency Only nine had full immunophenotyping performed and two of these had a picture of cDGS.
A further five of eight patients dying in infancy had marked lymphopenia but did not have lymphocyte phenotyping performed so it is possible that the incidence of cDGS was higher. The authors do however concede that this series of patients referred to a specialist center might present a biased view. Nevertheless, the proportion of children with CHARGE syndrome affected by a significant immunodeficiency is probably at least as high as the proportion in DGS associated with 22q deletion.
This conclusion would be consistent with the report of a series of 54 cases of patients referred for thymus transplantation for cDGS where the numbers of CHARGE and of 22q deleted cases were roughly in proportion to the incidences of the two genetic defects Immunodeficiency in Partial DGS The majority of children with thymic insufficiency as part of DGS, whatever the underlying cause, will have only a partial form of immunodeficiency.
The consequences are an increased susceptibility to infections and sometimes immunodysregulation resulting in autoimmunity. A wide range of T-cell immunity is seen in pDGS from near normal to near completely deficient.
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 There may be a small subset of more severely deficient 22q.
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 Otherwise there is no correlation between the severity of immunodeficiency and the clinical phenotype in regard the other features of DGS Most pDGS patients do not suffer opportunistic or life-threatening infections.
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 , As is the case with other partial T-cell deficient states, autoimmune disease can occur in pDGS.
The mechanism by which tolerance breaks down leading to autoimmunity in pDGS is not clear. Many forms of primary immunodeficiency are associated with an increased risk of autoimmune disease including conditions not associated with dysregulation of T cells.
However, in pDGS autoimmunity is not predominantly found in those with the most severe or frequent infections 65 , It is more likely that disturbance of central or peripheral tolerance or both occur as a consequence of the thymic abnormality. In the normal situation, central tolerance is generated through the presentation of tissue specific peptides to developing thymocytes by medullary thymic epithelial cells in the context of autologous major histocompatibility antigens and under the regulation of the autoimmune regulator AIRE.
There is subsequent deletion negative selection of thymocytes recognizing these self-antigens. In pDGS, negative selection must occur in relation to most antigens since the autoimmune disease seen is usually limited to one or two organs or systems.
By contrast, in autoimmune polyglandular syndrome type 1 APS-1 78 caused by mutations in the AIRE gene, multiple autoimmune disorders are typical.
Breakdown of peripheral tolerance is another possible explanation for autoimmunity in pDGS. The levels of these cells correlated closely with the numbers of recent thymic emigrant cells suggesting they were at least partially thymus derived In both studies these populations were present in reduced numbers in pDGS patients compared to controls at all ages but there was no difference between the levels in patients with and without autoimmunity.
Immunological assessment of pDGS patients often shows low overall numbers of T cells compared to normal with a tendency to improve after the first year of life, although in 10p deletion syndrome a progressive T-cell lymphopenia has been reported Mitogen responsiveness is generally normal in pDGS 80 , An increase in T-cell numbers with age may in part be due to the development of oligoclonal expansions resulting in abnormal T-cell receptor spectratypes.
Humoral immune defects and disturbance of B-cell immunity were recognized very early on after DGS was first described These may be relevant to the types of infections suffered. A number of relatively small series have looked at immunoglobulin and antibody levels in DGS associated with 22q. Low immunoglobulin levels were reported with variable frequency, most commonly affecting IgM but also occasionally causing a sufficiently low IgG to merit immunoglobulin replacement therapy.
Defective antibody responses to polysaccharide antigens were reported in a significant minority of patients.
A recently published, much larger study reported on over patients, with a median age of 3 years, from the European Society for Immunodeficiency and US Immunodeficiency Network Forty two percent were recorded as having 22q.
Overall, 2. In the over 3 years age group 6. Amongst patients over 3 years of age, around 0. There was no association between low immunoglobulin levels, in any of the isotypes, and T-cell counts nor between low T-cell counts and immunoglobulin levels. The authors acknowledged that the data were incomplete and that there may have been some reporting bias in that these patients were registered through immunodeficiency networks.
Nevertheless, this study provides the best estimate of the prevalence of humoral immune deficit in DGS.
B-cell numbers were not reported in this study but in another study were found to be generally normal though sometimes low in the first year of life, normalizing later The repertoire of IgH usage is also normal but further diversification through somatic hypermutation is deficient It has also been shown that the maturation of B-cells toward a memory phenotype is impaired in pDGS Given the specific role of the thymus in T- but not B-cell development it is probable, but not proven, that B-cell abnormalities are secondary to the T-cell deficiency in these patients.
Affected patients suffer opportunistic infections and, like other infants with SCID, are likely to die early unless they can be treated with a corrective procedure. In addition to susceptibility to infections these patients are at risk from transfusion acquired graft versus host disease B cells are usually present in normal numbers and NK cells in normal or high numbers.
In a proportion of cases there may be some mature T cells present either through maternal engraftment 94 or through oligoclonal expansion of memory phenotype T cells which have developed without thymic processing In the latter case, as in SCID these cells can mediate severe inflammation leading to an Omenn-like picture with erythrodermic rashes, enteropathy, and lymphadenopathy 53 , 96 This is called atypical cDGS.
An example of the abnormal spectratype in an atypical cDGS patient is shown in Figure 1 which can be compared to the normal spectratype achieved in the same patient after successful thymus transplantation Figure 2. Mitogen responsiveness is usually, but not invariably, impaired in these atypical patients Patient with atypical cDGS showing very abnormal spectratype with several completely missing families and abnormal skewed distribution in other families. T-cell receptor spectratyping performed as in legend to Figure 1.