digeorage 1

Immunologic Aspects ofDiGeorge SyndromeNicola A.M. Bobey-

Wright, MD,* Haig

Tcheurekdjian, MD,†

Diane Wara, MD,‡ David

B. Lewis, MD*

Author Disclosure

Drs Bobey-Wright,

Tcheurekdjian, Wara,

and Lewis did not

disclose any financial

relationships relevant

to this article.

Objectives After completing this article, readers should be able to:

1. Describe the immune defects seen in DiGeorge syndrome.2. Review recommended immune testing and immune follow-up in patients with

DiGeorge syndrome.3. Review the indications for screening for DiGeorge syndrome.4. Describe the variety of other congenital defects that can be associated with DiGeorge

syndrome.5. Review recommended anticipatory guidance for patients with DiGeorge syndrome.

IntroductionDiGeorge syndrome (DGS) is a contiguous field defect of the third and fourth pharyngealpouches, most often due to a hemizygous microdeletion in the chromosome 22q11.2region. Although classically defined as the triad of conotruncal cardiac anomaly, thymichypoplasia, and hypocalcemia, the syndrome encompasses a broad spectrum of congenitaldefects that have varying degrees of severity. Speech delay and dysmorphic features are twoof the most common and consistent findings. It shares phenotypic features with velocar-diofacial syndrome, conotruncal anomaly face syndrome, Opitz-G syndrome, CHARGEsyndrome, and cranio-cerebello-cardiac dysplasia syndrome. In some patients, these othersyndromes are the result of the same 22q11.2 microdeletion and may represent variationin the presentation of DGS rather than separate syndromes. This review focuses on theimmune defects seen in the patient population with hemizygous 22q11.2 microdeletion.

Causative FactorsThe underlying defect of DGS is due to inadequate contribution of neural crest tissue tothe third and fourth pharyngeal pouches that contribute to facial, cardiac, thymic, and

parathyroid tissues. DGS can be caused by either geneticdefects or environmental exposures in utero. Fetal exposureto ethanol, retinoids, and maternal diabetes can result in aclinical DGS phenotype. In more than 90% of patients,however, the syndrome results from hemizygosity at thechromosome 22q11.2 region (del22q11.2). In a small sub-set of patients, a deletion of 10p13 has been identified as thecausative factor, as has monosomy 18q21.33 and trisomy 18.No genetic or environmental cause can be identified in asmall percentage of patients.

The specific gene defects that explain the manifestationsof the DGS phenotype remain poorly understood. Patientswho have del22q11.2 most commonly have a 3-megabasedeletion involving at least 27 genes, although the smallestdeletion reported is 250 kilobases (kb). Severity of pheno-type does not correlate with the size of deletion, and patientswho have similar phenotypes have been found to have non-

*Division of Immunology and Transplantation Biology, Department of Pediatrics, Stanford University School of Medicine,Stanford, Calif.†Division of Allergy and Immunology, Department of Medicine, University of California, San Francisco; Division of Allergy andImmunology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.‡Division of Immunology and Rheumatology, Department of Pediatrics, University of California, San Francisco.

Abbreviations

CHD: congenital heart defectCMV: cytomegalovirusdel22q11.2: microdeletion of the chromosome

22q11.2 regionDGS: DiGeorge syndromeFISH: fluorescence in situ hybridizationIg: immunoglobulinMHC: major histocompatibility complexTCR: T-cell receptorTREC: T-cell receptor excision circleVPI: velopharyngeal insufficiencyVSD: ventricular septal defect

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overlapping deletions. A number of candidate genes havebeen investigated, but to date, none has been shownunequivocally to explain the phenotype completely. Themost promising is TBX1, a member of the T-box tran-scription factor, in which haploinsufficiency in micecauses a DGS-like phenotype. Three isolated point mu-tations of TBX1 also recently have been identified inseveral patients who have DGS. Nevertheless, it is un-likely that haploinsufficiency of a single gene can explaincompletely the DiGeorge phenotype based on the di-verse array of deletions in the 22q11.2 region that cancause the syndrome, the phenotypic variability within thesyndrome, and the discordance seen among patients whohave the same deletion. The full syndrome likely requiresinvolvement of numerous genes within the microdele-tion region and is probably substantially influenced bymodifying genes outside of the microdeletion region.

IncidenceFluorescence in situ hybridization (FISH) testing in thelast decade has shown that the hemizygous del22q11.2 isone of the most common genetic defects seen in humans.The incidence has been found to be as high as 1 in 4,000,although it is very difficult to estimate due to the ex-tremely variable phenotype and inconsistent screeningpractices. Inheritance is autosomal dominant, with mostdeletions being spontaneous. Familial transmission isestimated to occur in only 8% to 28% of cases. Thesyndrome occurs equally in males and females and has noknown racial predisposition.

Normal T-cell Ontogeny and FunctionThymocyte development is initiated when prothymo-cytes derived from bone marrow or fetal liver hematopoi-etic stem cells enter the thymus. This begins at 7 weeks’gestation. The thymus serves as a site for thymocyteproliferation and creation of the T-cell receptor (TCR)repertoire through somatic rearrangement of the TCRgenes. Thymocytes that express surface TCR that canrecognize peptides associated with self major histocom-patibility complex (MHC) are selected positively in thethymic cortex for survival as part of an “education”process. This is followed by a negative selection processin which thymocytes that have too strong an affinity forself peptide/self MHC complexes are selected negativelyby apoptosis, an important mechanism for limiting auto-immunity. Thymocytes that survive these two selectionmechanisms enter the peripheral blood as recent thymicemigrant cells and colonize the peripheral lymphoid or-gans. The end result is that each person has a diverse arrayof unique T cells that can recognize the myriad microor-

ganisms and foreign antigens in the environment buthave a limited ability to respond to self-peptides.

T cells are instrumental for appropriate functioning ofthe cell-mediated and humoral arms of the immunesystem by directing the functioning of other immunecells (helper functions) and by destroying host cells in-fected with viruses (cytotoxic functions). Production ofantibodies by B cells to most protein antigens is depen-dent on CD4 T-cell signals, so severe T-cell disordersusually result in concomitant abnormalities of humoralimmunity. Furthermore, T cells are intimately involvedin limiting tumor induction by certain viruses, such asEpstein-Barr virus, as well as the regulation of self-reactive T and B lymphocytes that cause autoimmunedisorders.

Immunodeficiency of DiGeorge SyndromeThe immunodeficiency of DGS is due primarily to re-duced production of mature thymocytes from less ma-ture precursors in the thymus. Most results suggest thatthe T cells produced and found in the periphery have noinherent functional defect. The fact that transplantationof T-cell-depleted allogeneic thymic tissue into DGSpatients can lead to reconstitution of the T-cell compart-ment is consistent with the deficiency primarily involvingnonhematopoietic cells rather than hematopoietic cells.

Patients who have DGS present with a spectrum ofimmunodeficiency ranging from nearly normal to severe,life-threatening conditions. Although those who havesevere immunodeficiency represent fewer than 1% of allDGS patients, their early identification is essential toprevent and treat life-threatening infections and to planfor immune reconstitution. Affected patients presentwith profoundly decreased T-cell numbers (�50/mm3),depressed T-cell function (as measured by lymphocyteproliferation assays, such as with mitogens), and oftenconcomitantly low immunoglobulin (Ig) levels. The pa-tients are at high risk for the development of dissemi-nated and life-threatening infections with organisms thatrequire an intact cell-mediated immune system for erad-ication, such as cytomegalovirus, adenovirus, or Pneumo-cystis jiroveci (formerly P carinii). Graft-versus-host dis-ease also may be found due to transplacental transfer andengraftment of maternal T cells, leading to the typicalrash and diarrhea seen in other forms of graft-versus-hostdisease.

A rare subset of DGS patients who have the severeimmunodeficiency phenotype have an atypical presenta-tion of DGS that includes rash, lymphadenopathy, andoligoclonal T cells. They may have normal or near-normal T-cell numbers and functional studies that are

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not antigen-specific. The T cells in these patients are notderived from normal maturation and selection in thethymus, but rather are a result of extrathymic prolifera-tion of a very small number of clonal T cells. Thus, theyexhibit a restricted TCR repertoire and are unable torecognize and respond appropriately to most microor-ganisms and antigens. This can be one of the mostdifficult presentations of DGS to manage and is associ-ated with significant morbidity and mortality.

In contrast to severely affected patients, most patientswho have DGS present with measurable T-cell numbersand function ranging from low to near-normal. Theyrarely have an increased risk of opportunistic infections,but are at higher risk for the development of recurrentsinopulmonary infections such as otitis media, sinusitis,and bronchitis. Recurrent bacterial infections are likelydue to both anatomic abnormalities of the airway and anunderlying humoral immunodeficiency, but not clini-cally relevant T-cell dysfunction, as evidenced by thedemonstration of no correlation between measured cel-lular immune function and number or severity of sino-pulmonary infections. Immune function tends to im-prove through infancy, and by 3 years of age, mostpatients tend to have near-normal T-cell counts andfunction.

Most patients who have DGS have reduced thymicproduction of naı̈ve T cells, as assessed by flow cytometricquantification of CD45RA�CD62L� T cells that haverecently exited the thymus. Thymic function also can beassessed by measuring peripheral blood TCR excisioncircles (TRECs), which are a normal byproduct of so-matic recombination of the TCR genes in the thymus.TRECs persist in newly formed naı̈ve T cells and arediluted by cell division as they undergo replication alongwith the cell’s genomic DNA. TREC content can bequantitated from peripheral blood by real-time polymer-ase chain reaction, and DGS patients have lower valuesthan healthy controls, consistent with reduced thymicproduction of peripheral T cells. Decreased thymic out-put may result in reduced diversity of the TCR repertoireof naı̈ve T cells.

AutoimmunityPerhaps the most telling sign of a subtly dysfunctionalimmune system in patients who have DGS is the high riskof autoimmune disease evident later in life. More than10% of patients develop autoimmune disease, most com-monly autoimmune cytopenias. The risk of immunethrombocytopenic purpura is 200 times that of the nor-mal population. Juvenile rheumatoid arthritis may be20 times more frequent in DGS patients than the general

population, and other autoimmune diseases, includingGraves disease and type 1 diabetes mellitus, also havebeen reported. Decreased numbers of CD4�CD25�regulatory T cells, which function to suppress autoreac-tive lymphocytes, have been noted in patients who haveDGS and may contribute to the increased risk of auto-immune disease.

Humoral ImmunityAbnormalities in humoral immunity, as evidenced byabnormal Ig production, have been identified in up to40% of patients who have del22q11.2, although this maypredispose to recurrent infections in fewer than one thirdof the patients. Ig A deficiency is a common finding, witha prevalence of 13%. When patients who have recurrentsinopulmonary infections are evaluated as a separategroup, more than 50% may have poor immune responseto purified polysaccharide antigens such as the 23-valentStreptococcus pneumoniae vaccine. Restricted Ig reper-toire also has been shown, akin to the restricted TCRrepertoire. It is important to identify such patients be-cause they may benefit from antimicrobial prophylaxis orIg replacement therapy.

DiagnosisThe diagnosis of DGS is based on the identification oftypical clinical and laboratory features. Genetic analysesare adjuncts to aid in diagnosis because some patients inwhom a chromosomal abnormality is not identifiedclearly fit the DGS phenotype. Because there are no strictcriteria, the diagnosis is based on identifying a constella-tion of findings generally agreed to encompass the im-portant abnormalities of the syndrome. These include(to varying degrees): facial dysplasia, cardiac anomalies,hypoparathyroidism, hypoplastic or absent thymus, anddevelopmental delay.

Dysmorphic FeaturesBecause the facial dysplasia seen in DGS can be so mild asto be missed on routine examination, careful physicalexamination is important. Dysmorphic features may be-come more prominent with age. Characteristic featuresinclude low-set, posteriorly rotated, elfinlike ears; bul-bous nose with lateral build-up of the nasal bridge (tube-like morphology); hypertelorism; micrognathia; and ashort philtrum).

Cardiac DefectsDGS is the second most common cause of congenitalheart defects (CHDs) after trisomy 21, occurring in 5%of children who have CHDs. The classic cardiac defects





are conotruncal abnormalities, although it now is recog-nized that the spectrum of cardiac anomalies is variable,with only two thirds of patients who have heart abnor-malities having a conotruncal defect. Tetralogy of Fallotis the most common, occurring in nearly 20% of patients.Approximately 15% of patients have either an interruptedaortic arch type B or a ventricular septal defect (VSD).Pulmonary atresia with VSD and truncus arteriosus arethe next most common defects, both with an incidenceof nearly 10%. Patients who test positive for DGS gener-ally also have other features of the disorder. Therefore,screening of patients who have any type of CHD (otherthan isolated secundum type atrioseptal defect or patentductus arteriosus, which are not associated with thesyndrome) for other features of DGS is recommended.Approximately 20% of patients who have the del22q11.2have no cardiac defect.

HypoparathyroidismHypoparathyroidism is reported in 60% of patients whohave DGS, generally in the neonatal period. Up to 40% ofpatients experience seizures due to hypocalcemia. Thehypocalcemia resolves over the first postnatal year in 70%of patients, although some require long-term calciumsupplementation. It now is recognized that some pa-tients can develop hypocalcemia in adulthood, particu-larly during times of physiologic stress. Hypoparathy-roidism should be confirmed by measurement ofparathyroid hormone concentrations. Challenge withcalcium chelators can unmask latent or subclinical hypo-parathyroidism in patients who have normal calcium andparathyroid hormone concentrations; these patientseventually may develop episodes of hypocalcemia. Be-cause there are few other causes of hypocalcemia in termneonates, DGS should be considered in any neonate whoexhibits low calcium values. Recent reports suggest it alsoshould be considered in adults presenting with hypocal-cemia in whom other causes are ruled out.

ImmunodeficiencyAs previously noted, clinically relevant T-cell dysfunctionis present in only a minority of patients. Severely affectedpatients either have profoundly low T-cell numbers andproportionally poor T-cell function or, rarely, low num-bers of recent thymic emigrants and TRECs in the pres-ence of normal-appearing T-cell numbers and function.Coordination of care with a referral center may be nec-essary for these specialized studies of thymic function.

Although many patients who have DGS have near-normal T-cell numbers and function, they must be eval-uated thoroughly to ensure immunocompetency. Assess-

ment of T and B lymphocyte populations is imperative,and lymphocyte proliferation assays to assess T-cell func-tion, including to antigens, is recommended where avail-able. A one-time evaluation rarely is adequate to deter-mine the extent of immunodeficiency. Therefore, serialclinical and laboratory evaluations, in consultation withan individual experienced in the care of these patients, areobligatory.

The humoral immune system should be assessedthrough measurement of quantitative Igs (IgG, IgA, andIgM) and, when indicated, specific antibody responses topolysaccharide and protein antigens such as the pneumo-coccal and tetanus vaccines. Care must be taken to inter-pret these results in relation to the patient’s age andcorresponding level of immune development; consulta-tion with a pediatric immunologist is recommended.

Otolaryngeal and Airway AbnormalitiesOtolaryngeal anomalies are frequent, occurring in almost50% of patients. A submucosal or overt cleft palate is seenin 16% and 11% of patients, respectively. These palatalabnormalities may lead to velopharyngeal insufficiency(VPI), but even those who do not have an identifiablecleft palate can have VPI due to poor muscular tone ofthe velopharynx. In fact, 38% of individuals who haveVPI of unknown cause and 64% of patients who have VPIfollowing adenoidectomy have been found to havedel22q11.2. These anomalies can contribute to recurrentotitis media or sinusitis, poor feeding, and poor speech;such patients should be referred to an ear-nose-throatservice for evaluation and management.

A strong association recently has been found betweenthe presence of anterior glottic webs and del22q11.2,with 65% of children who have anterior glottic webshaving del22q11.2. Other airway abnormalities, includ-ing laryngeal webs and tracheomalacia, also can occur.

Finally, hearing deficits are common and multifacto-rial in this population due to both ear abnormalities andrecurrent otitis media. Audiologic assessment and closefollow-up of hearing is recommended.

Neurologic AbnormalitiesOnly 20% of patients who have DGS have completelynormal neurologic function. Speech delay is one of themost common features of the syndrome. Developmentalprogress is variable, with 20% of patients havingmoderate-to-severe learning difficulties and the remain-ing 60% having only mild difficulties. Behavior and psy-chiatric issues are common, occurring in 10% of patientsand including attention-deficit disorder, psychosis, ma-jor depressive disorders, and schizophrenia.





Renal and Genitourinary DefectsRenal abnormalities are common, occurring in 36% ofpatients, and include absent, dysplastic, or multicystickidneys; obstructive abnormalities; and vesicoureteric re-flux. Eight percent of males have undescended testes.Renal imaging, therefore, is recommended for any pa-tient diagnosed with DGS.

Other AbnormalitiesDefects have been reported in nearly every organ systemin patients who have DGS, including gastrointestinalabnormalities, skeletal defects, coloboma, giant plateletsand mild thrombocytopenia, and growth hormone defi-ciency.

Prenatal DiagnosisAlthough the 22q11.2 deletion is frequently a de novodeletion, it also can be inherited in an autosomal domi-nant pattern. In some cases, the parent may lack overtclinical features of DGS. Affected individuals have a 50%chance of transmitting the deletion to their offspring.FISH studies can be performed on cells obtained bychorionic villus sampling between 10 and 12 weeks’gestation or by amniocentesis at later gestational ages. Itshould be noted that although prenatal testing can iden-tify affected fetuses accurately, this testing offers nopredictive data on the expected severity of the pheno-type.

ManagementAll patients suspected of having DGS should undergo aFISH assay to look for hemizygosity at the chromosome22q11.2 region. If this deletion is not found, a FISHassay for 10p13–14 deletion and high-resolution karyo-type should be pursued. Indications for testing are listedin Table 1.

A multidisciplinary approach is required for the man-agement of neonates who have DGS (Table 2). Becauseearly mortality is usually due to cardiac disease, early andaggressive attention must be given to cardiac evaluation.The most common cause of death after 5 months of ageis infection. Therefore, immune evaluation should occurpromptly after birth to allow rapid initiation of preven-tive measures and aggressive treatment of possible infec-tions. Although chest radiography frequently is obtainedto assess for the presence of a thymic shadow, absence ofa thymic shadow rarely correlates with the severity ofimmunodeficiency due to the presence of functional,ectopic thymic tissue. Functional studies of thymic func-tion are a more reliable method of assessing immunefunction.

All patients suspected of having DGS should receivecytomegalovirus (CMV)-negative, irradiated, andleukocyte-filtered blood products until confirmation of acompetent immune system. There is a potential risk of

Table 1. Indications for GeneticTesting for DiGeorge SyndromeCongenital Heart Disease

� Tetralogy of Fallot� Interrupted aortic arch type B� Other conotruncal heart defects� Truncus arteriosus, pulmonary atresia with

ventriculoseptal defect, right-sided aortic arch� Other congenital heart defects except isolated

secundum atrial septal defect or patent ductusarteriosus*

Hypocalcemia

Immune Defect

� T-cell lymphopenia*� Humoral immune defect*� Absent thymus noted on diagnostic imaging studies

or at cardiac surgery� Recurrent sinopulmonary infections or opportunistic

infections*� Autoimmune disease, especially autoimmune

cytopenias*

Airway Abnormalities

� Anterior glottic webs� Cleft palate*� Velopharyngeal insufficiency*� Other airway abnormalities*

Dysmorphic Features

� Lateral build-up of nasal bridge� Hypertelorism, micrognathia, short philtrum, low-set

posteriorly rotated ears, defective pinna

Developmental Delay*

� Speech delay*

Positive Family History

� Also consider DGS if history of fetal exposure toethanol, retinoids, and maternal diabetes*

Testing should include:

� FISH for hemizygosity at the 22q11.2 regionIf strong suspicion and FISH for 22q11.2 is normal:� FISH for 10p13 deletion� High-resolution karyotype of 22q11.2 region

*If associated with other features of the syndromeFISH�fluorescence in situ hybridization





graft-versus-host disease due to the presence of a smallnumber of functional leukocytes in nonirradiated bloodproducts, and patients are at risk for disseminated CMVinfection if they have a significant defect of cell-mediatedimmunity.

Thymic TransplantationThymic transplantation has been used experimentally forthe treatment of DGS patients who have severe immu-nodeficiency. There are several reports of successfultransplant using fetal thymic tissue, but such donor tissueis obviously difficult to obtain. Alternatively, thymic tis-sue is obtained from infants who have CHDs in whom asubtotal thymectomy is performed routinely at the timeof their corrective cardiac surgery. The thymic tissue iscultured, allowing removal of donor lymphocytes, andsurgically inserted into the quadriceps muscles of therecipient. The importance of matching of human leuko-cyte antigen alleles between donor and recipient is cur-rently unknown. Thymopoiesis of host cells has beendemonstrated within the donor tissue, and recovery of

immune function within weeks to months posttransplanthas been documented by increased T-cell numbers andimproved function, increased numbers of CD45RA�CD62L� naı̈ve T cells, increased TRECs, and normal-ization of the T-cell repertoire. Currently, thymic trans-plantation is only available on an experimental basis at afew specialized centers and should be considered onlyafter consultation with an expert in the field. Thymictransplantation is recommended for patients who havesevere thymic hypoplasia or aplasia, as evidenced by:1) significantly decreased T-cell numbers, 2) fewer than50 naı̈ve CD45RA� CD62L� T cells/mm3; and3) fewer than 100 TRECs/1�105 T cells. The assess-ment of TRECs is currently only available as a researchtest.

Hematopoietic Stem Cell TransplantationHematopoietic stem cell transplantation also has beenused in rare cases for immune reconstitution. Bone mar-row transplant has been performed on fewer than 10patients, with only three reported in the literature. Be-cause bone marrow transplant often results in mixedchimeras, it has been theorized that immune reconstitu-tion was due to infusion of mature T cells from the donorrather than engraftment of hematopoietic cells. Cur-rently, thymic tissue transplant is performed more fre-quently than hematopoietic stem cell transplant for res-cue of patients who have severe immune defects.

Follow-up CareRepeated assessment of the immune system by an immu-nologist during the first several years after birth is recom-mended (Table 3). For patients who have severe immu-nodeficiency, thymic transplantation may be considered.For patients who have moderate-to-severe immunodefi-ciency, management may include prophylaxis for Pjiroveci, respiratory syncytial virus prophylaxis, gamma-globulin replacement for significant humoral deficiency,and possibly prophylactic antibiotics. Live-virus vaccinesshould be withheld during the first postnatal year, andexposure to varicella should be treated with eithervaricella-zoster immunoglobulin or acyclovir. For infantswho have significant immunodeficiency, we also recom-mend avoiding sick contacts; minimizing exposure topublic places and school-age children; and frequenthandwashing for the patient, caregivers, and visitors.Group child care should be avoided if possible.

Following the first postnatal year, the immune systemimproves in many affected children, and restrictions of-ten can be relaxed. If immune re-evaluation results arenormal, live vaccines may be administered. Some pa-

Table 2. Neonatal Management ofDiGeorge SyndromeAll Patients

� FISH for 22q11.2 deletion; if negative, karyotypeand FISH for 10p13-14 deletion

� Immune assessment� Complete blood count with differential count� T- and B-lymphocyte populations by flow

cytometry� Lymphocyte function (proliferation to mitogens)� IgG, IgA, IgM concentrations

� Echocardiography and formal cardiology evaluation� Measurement of calcium, phosphorus, and

parathyroid hormone level� Renal ultrasonography� Ear-nose-throat assessment for airway anomalies,

cleft palate, velopharyngeal insufficiency� Gastrointestinal evaluation if gastroesophageal

reflux or feeding issues as necessary� Central nervous system imaging if defect suspected

Suspected Severe Immunodeficiency

� Protective isolation precautions� Pneumocystis prophylaxis� Intravenous immunoglobulin replacement if

indicated� Aggressive treatment of infections, with search for

causative organism� Consultation with regional referral center for thymus

or bone marrow transplantation





tients, however, continue to have difficulties with recur-rent infections and should continue to have an immunol-ogist involved in their care.

As patients grow older, difficulties with infectionstend to resolve, although patients become at risk forautoimmune disease, which often is seen after the firstdecade of life. The threshold for investigation of possibleautoimmune complications should be low.

Patients continue to require multidisciplinary care asthey grow. Complications of immunodeficiency and car-

diac disease tend to be most troublesome initially, withother aspects of the syndrome, including problems withspeech delay and developmental delay, gastroesophagealreflux, and VPI, becoming more problematic in laterinfancy. Early enrollment in speech therapy and infantdevelopment programs is recommended; many childrenrequire special education programs at school. Finally,mental health complications such as schizophrenia maydevelop in adolescence or adulthood, requiring psychi-atric care.

Genetic counseling should not be neglected, particu-larly if a chromosomal deletion is identified. FISH testingshould be offered to parents, especially if they plan tohave more children. Testing of siblings may be war-ranted. Patients themselves should be educated as to therisk of having affected children once they come of repro-ductive age.

Suggested ReadingBotto LD, May K, Fernhoff PM, et al. A population-based study of

the 22q11.2 deletion: phenotype, incidence, and contributionto major birth defects in the population. Pediatrics. 2003;112:101–107

Junker AK, Driscoll DA. Humoral immunity in DiGeorge syn-drome. J Pediatr. 1995;127:231–237

Gennery AR, Barge D, O’Sullivan JJ, et al. Antibody deficiency andautoimmunity in 22q11.2 deletion syndrome. Arch Dis Child.2002;86:422–425

Goodship J, Cross I, LiLing J, Wren C. A population study ofchromosome 22q11 deletions in infancy. Arch Dis Child. 1998;79:348–351

Goodship RAK, Wilson JA, Philip DI, et al. Spectrum of clinicalfeatures associated with interstitial chromosome 22q11 dele-tions: a European collaborative study. J Med Genet. 1997;34:798–804

Markert ML, Alexieff MJ, Li J, et al. Complete DiGeorge syn-drome: development of rash, lymphadenopathy, and oligo-clonal T cells in 5 cases. J Allergy Clin Immunol. 2004;113:734–741

Markert ML, Boeck A, Hale LP, et al. Transplantation of thymustissue in complete DiGeorge syndrome. N Engl J Med. 1999;341:1180–1189

Markert ML, Sarzotti M, Ozaki DA, et al. Thymus transplantationin complete DiGeorge syndrome: immunologic and safety eval-uation in 12 patients. Blood. 2003;102:1121–1130

Maynard TM, Haskell GT, Lieberman JA, LaMantia A. 22q11.2DS: genomic mechanisms and gene function in DiGeorge/velocardiofacial syndrome. Int J Dev Neurosci. 2002;20:407–419

Miyamoto RC, Cotton RT, Rope AF, et al. Association of anteriorglottic webs with velocardiofacial syndrome (chromosome22q11.2 deletion). Otolaryngol Head Neck Surg. 2004;130:415–417

Perez EE, Bokszczanin A, McDonald-McGinn D, Zackai EH,Sullivan KE. Safety of live viral vaccines in patients with chro-mosome 22q11.2 deletion syndrome (DiGeorge syndrome/

Table 3. Care Beyond theNeonatal PeriodImmunology

� Reassessment of immune function every 3 to 6months until at least 2 years of age

� Testing for adequate response to inactivatedvaccines (eg, tetanus toxoid)

� Continuation of prophylactic therapies as necessary� Rapid assessment for possible infections and

aggressive therapy as necessary� Protective precautions: handwashing, avoidance of

sick contacts as necessary� Delayed administration of live-virus vaccines until

immune function is adequate*� Administration of cytomegalovirus-negative,

irradiated, leukocyte-filtered blood products ifneeded

Development

� Early speech therapy� Early developmental assessment and therapy as

required

Ear-Nose-Throat

� Follow-up for cleft palate, velopharyngealinsufficiency, and other airway anomalies

� Management of otitis media and sinusitis� Audiology assessment, especially if recurrent otitis

media

Endocrine

� Follow-up for hypoparathyroidism as necessary

Cardiology

� Follow-up as required for specific congenital defect

Adolescence

Primary physician should watch for late complications:� Autoimmune disease� Mental health complications (eg, schizophrenia)

*Varicella-zoster; measles, mumps, rubella; live polio vaccination; liveflu vaccination





velocardiofacial syndrome). Pediatrics. 2003;112:e325–327.Available at: http://pediatrics.aappublications.org/cgi/content/full/112/4/e325

Pierdominici M, Mazzetta F, Caprini E, et al. Biased T-cell receptorrepertoires in patients with chromosome 22q11.2 deletion syn-drome (DiGeorge syndrome/velocardiofacial syndrome). ClinExp Immunol. 2003;132:323–331

Ryan AK, Goodship JA Wilson DI, et al. Spectrum of clinicalfeatures associated with interstitial chromosome 22q11.2 dele-tions: a European collaborative study. J Med Genet. 1997;34:798–804

Sullivan KE, McDonald-McGinn D, Driscoll DA, et al. Longitudi-nal analysis of lymphocyte function and numbers in the first yearof life in chromosome 22q11.2 deletion syndrome (DiGeorgesyndrome/velocardiofacial syndrome). Clin Diagn Lab Immu-nol. 1999;6:906–911

Yagi H, Furutani Y, Hamada H, et al. Role of TBX1 in humandel22q11.2 syndrome. Lancet. 2003;362:1366–1373

Yamagishi H, Garg V, Matsuoka R, Thomas T, Srivastava D.A molecular pathway revealing a genetic basis for human cardiacand craniofacial defects. Science. 1999;283:1158–1161

Other Resources for Families and PhysiciansVelocardiofacial Syndrome Educational Foundationwww.vcfsef.orgPrimary Immune Deficiency Foundationwww.primaryimmune.orgNational Primary Immunodeficiency Resource Centerwww.info4pi.org

NeoReviews Quiz

9. The dysfunctional immune system in DiGeorge syndrome renders the affected infant susceptible to thedevelopment of autoimmune disease later in life. Of the following, the risk of autoimmune disease inDiGeorge syndrome relative to the general population is highest with:

A. Graves disease.B. Immune thrombocytopenic purpura.C. Juvenile rheumatoid arthritis.D. Multiple sclerosis.E. Type 1 diabetes mellitus.

10. Patients who have DiGeorge syndrome present with a spectrum of immunodeficiency ranging from nearlynormal to severe, life-threatening immunodeficiency. Of the following, the immunodeficiency in DiGeorgesyndrome is due primarily to:

A. Decreased production of mature thymocytes from their precursors.B. Deficiency of lymphoid structures necessary for optimal B-cell function.C. Dysfunction of B cells in relation to humoral immunity.D. Excess production of thymic naı̈ve T cells.E. Inherent defect in function of T cells in the periphery.

11. DiGeorge syndrome is the second most common cause of congenital heart defects after trisomy 21. Of thefollowing, the most common congenital heart defect in DiGeorge syndrome is:

A. Interrupted aortic arch.B. Pulmonary atresia.C. Tetralogy of Fallot.D. Truncus arteriosus.E. Ventricular septal defect.





DOI: 10.1542/neo.6-10-e4712005;6;e471NeoReviews

Nicola A.M. Bobey-Wright, Haig Tcheurekdjian, Diane Wara and David B. LewisImmunologic Aspects of DiGeorge Syndrome

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DOI: 10.1542/neo.6-10-e4712005;6;e471NeoReviews

Nicola A.M. Bobey-Wright, Haig Tcheurekdjian, Diane Wara and David B. LewisImmunologic Aspects of DiGeorge Syndrome

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ISSN: 1526-9906. 60007. Copyright © 2005 by the American Academy of Pediatrics. All rights reserved. Online the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,it has been published continuously since . Neoreviews is owned, published, and trademarked by Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication,


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