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DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis

DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis
Literature review current through: Jan 2024.
This topic last updated: Nov 07, 2023.

INTRODUCTION — DiGeorge syndrome (DGS) is a constellation of signs and symptoms associated with defective development of the pharyngeal pouch system. Most cases are caused by a heterozygous chromosomal deletion at 22q11.2. Chromosome 22q11.2 deletion syndrome (22qDS) includes DGS and other similar syndromes, such as velocardiofacial syndrome. The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia (resulting from parathyroid hypoplasia).

Thymic defects in DGS result in a range of T cell deficits. Most patients with DGS have mild defects in T cell numbers and are not severely immunodeficient. Approximately 1 percent, however, have a complete absence of thymic tissue and profound immunodeficiency. This form of DGS, called complete DGS, is a type of congenital athymia with a severe combined immunodeficiency (SCID) phenotype and is life threatening if not corrected with immune reconstitution by thymic tissue implantation or potentially hematopoietic cell transplantation in some instances. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

This topic reviews the clinical features and diagnosis of DGS. The epidemiology, pathogenesis, management, and prognosis of patients with DGS are presented separately. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis".)

CLINICAL PRESENTATION — The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia, and they are diagnosed in early life [1]. However, the phenotype is quite variable (table 1), and there may be marked differences between affected persons, even within a single family [2-7]. A broad spectrum characterizes the presence and severity of individual features, and the severity of each feature appears to be independent of other features. Older children with DGS may be detected through clinics for congenital heart defects or craniofacial clinics, may be referred to developmental specialists for poor school performance, or may be diagnosed due to frequent infections or autoimmune conditions.

Cardiac anomalies — Conotruncal cardiac defects occur in approximately 80 percent of DGS patients and, when present, are typically the initial abnormalities noted [2,3,5]. The term "conotruncal" refers to the distal portion of the fetal heart (trunco-aortic sac) at an early stage in development. The aortic and pulmonary roots subsequently develop from this area, and defects in these structures are referred to as conotruncal defects.

The most common cardiac defects account for two-thirds of the cardiac anomalies seen in patients with DGS and include the following [2,3,5,8,9]:

Interrupted aortic arch

Truncus arteriosus

Tetralogy of Fallot

Atrial or ventricular septal defects (ASDs or VSDs)

Vascular rings

The first three defects listed cause cyanotic heart disease in the newborn. Infants with an interrupted aortic arch may present with differential cyanosis, in which the upper half of the body is pink and the lower half is blue. (See "Cardiac causes of cyanosis in the newborn" and "Truncus arteriosus" and "Congenital and pediatric coronary artery abnormalities".)

Most children with small ASDs and VSDs are asymptomatic, but infants with large defects may present with heart failure, failure to thrive, and/or respiratory distress. (See "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis", section on 'Presentation' and "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis", section on 'Presentation'.)

The clinical presentation of vascular rings varies depending upon the degree of tracheal and esophageal compression and can range from critical airway obstruction to stridor and feeding issues. Patients with incomplete vascular rings may be asymptomatic. (See "Vascular rings and slings" and "Congenital and pediatric coronary artery abnormalities".)

Hypocalcemia — Hypocalcemia, resulting from underdevelopment of the parathyroid glands, is another potentially life-threatening manifestation of DGS. This develops in the newborn period in up to 60 percent of DGS patients and may present with jitteriness, tetany, or seizures, with low serum calcium, elevated serum phosphorus, and very low parathyroid hormone levels. (See "Clinical manifestations of hypocalcemia".)

Complications of hypocalcemia are unusual later in life, secondary to presumed compensatory hyperplasia of existing parathyroid tissue. However, hypocalcemia can be precipitated by extreme stress in older patients [10]. Rarely, complications of hypocalcemia are the presenting symptoms in adults with undiagnosed 22qDS [11]. (See "Parathyroid hormone secretion and action".)

Hypoplastic/aplastic thymus — In most patients with DGS, the thymus is present, although it is often reported as hypoplastic. However, the definition of thymic hypoplasia is inexact since there are limited studies, particularly in children, to support the definition of a diminished size of the thymus in any condition or in normal individuals [12,13]. The thymus is completely absent in a rare subset of patients with DGS. One study characterizing fetal thymic size for at-risk pregnancies found that the presence of normal thymic tissue mass was associated with normal or near-normal T cell counts at birth [14]. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Thymic hypoplasia' and "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Immune function'.)

Immunodeficiency — Immunodeficiency is common in patients with DGS and can range from prolonged and recurrent sinopulmonary infections (often termed partial DGS) to congenital athymia (a severe combined immunodeficiency [SCID] like phenotype termed complete DGS). The severity of the immunodeficiency is related to the degree of thymic function. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Thymic hypoplasia' and "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Immune function'.)

Complete DGS — Complete DGS is found in less than 1 percent of patients with 22qDS and is a form of congenital athymia. The thymus is absent, and the T cell count is <3 standard deviations below normal for age (typically <50 CD3+ T cells/mm3) in these patients. In a large series of patients with complete DGS, 52 percent had an identifiable 22q11.2 deletion, while the remaining 48 percent did not have an identifiable chromosomal problem at the time of the study [15]. Infants with complete DGS are detected by SCID newborn screening (NBS) using an assay for T cell receptor excision circles (TRECs), a biomarker of T cell development/thymopoiesis [16,17]. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)

In the absence of screening, infants with complete DGS are diagnosed following the development of recurrent severe infections, chronic diarrhea, and failure to thrive. This form of DGS is fatal unless recognized promptly after birth and treated with thymic tissue implantation or bone marrow transplant. (See 'Evaluation in neonates' below and "Severe combined immunodeficiency (SCID): An overview" and "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis", section on 'Immunologic management of complete DGS'.)

"Atypical" complete DGS — A subset of patients with severe T cell deficiency, detectable by SCID newborn screening, present with or develop a leaky form of SCID phenotype, typically referred to as atypical complete DGS [18-21]. These patients have oligoclonal populations of T cells detectable in the peripheral blood, lymphadenopathy, and a generalized dermatitis [22]. Their T cells respond poorly to mitogens in vitro, and there is no evidence for maternal engraftment. Patients with atypical complete DGS can present with erythroderma, oligoclonal T cell expansion, lymphadenopathy, and elevated serum immunoglobulin E (IgE) levels and may be best classified as Omenn-like syndrome. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T-B-NK+ SCID without radiation sensitivity due to RAG defects (includes most cases of Omenn syndrome)' and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Omenn syndrome phenotype'.)

Partial DGS — Overall, approximately 75 percent of patients with 22qDS have some degree of thymic insufficiency [2]. Partial DGS infants with the lowest production of T cells will be identified by SCID NBS [16]. The exact proportion of cases detected by NBS depends upon the screening TREC cutoff, which is determined by individual state screening programs in the United States. Impaired T cell production occurs in most infants with partial DGS, although CD3+ T cell counts tend to improve gradually or stabilize over time and can approach age-related normal levels. The improvement in CD3+ T cell counts reflects decreased age-related decline in T cell counts and increased accumulation of memory T cells secondary to lymphocytic homeostatic proliferation [23]. T cell function may also be abnormal, although the deficiency is not usually severe [24]. Most patients with partial DGS do not suffer from opportunistic or life-threatening infections [25]. However, many patients with partial DGS have a history of recurrent sinopulmonary infections and prolonged respiratory viral illnesses [26]. Humoral immunodeficiencies are associated with partial DGS, including an increased prevalence of immunoglobulin A (IgA) deficiency and functional antibody defects (ie, polysaccharide antibody deficiency) [27-30]. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Partial DGS'.)

In one study, up to one-third of patients had either recurrent sinusitis or otitis media, and a minority had bronchitis or pneumonia [29]. Recurrent and chronic sinusitis appears to be related to palatal abnormalities or gastroesophageal reflux in some patients, although polysaccharide antibody deficiency is also seen. (See "Specific antibody deficiency" and "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis".)

Other immune-related problems — An increased incidence of autoimmune and atopic disease is seen in patients with DGS.

Autoimmune disease — Multiple retrospective and prospective studies have demonstrated an increased incidence of autoimmune phenomenon in patients with DGS and 22qDS, estimated at 10 percent [27,29,31-38], suggesting an underlying defect in immune regulation [23,39,40]. Studies are ongoing to better define the mechanism(s) of immune dysregulation. Impaired central and peripheral tolerance is implicated as the underlying mechanism for increased autoimmune disease, but this remains poorly defined [41-43]. A case-control, multicenter study demonstrated distinct immune phenotypes in patients with DGS and autoimmune hemolytic anemia (AIHA) compared with those without AIHA. The immune differences predated the development of AIHA. This observation implies that a patient's immunophenotype may allow prognostication for the risk of developing autoimmune disease [44]. The autoimmune diseases that are reported at an increased frequency in this population include autoimmune cytopenias, arthritis, enteropathy, and autoimmune thyroid disease. Several case reports have documented that an autoimmune manifestation was the presenting symptom leading to the diagnosis of 22qDS [45,46]. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Partial DGS' and "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

Allergic disease — Atopic disease may also be a feature of 22qDS. One study demonstrated an increased incidence of asthma and eczema, but not allergic rhinitis, in 22qDS patients compared with the sibling control group [47]. The underlying proposed mechanism is preferential skewing toward T helper cell type 2 (Th2) differentiation due to the increased homeostatic proliferation observed in 22qDS patients [40].

Craniofacial abnormalities — Possible facial abnormalities include low-set and posteriorly rotated ears, ocular hypertelorism, and a bulbous nasal tip (table 2 and picture 1). These phenotypic findings are not specific for DGS and can be less pronounced in some populations [48]. Similar features may be seen in patients with other 22qDS, such as velocardiofacial syndrome, Opitz G/BBB syndrome, and Cayler cardiofacial syndrome. Nasal dysmorphism, for example, was the one consistent finding in a series of 225 patients with 22q11.2 deletions [49]. The facial features in DGS often become less pronounced with age (picture 1). (See "Syndromes with craniofacial abnormalities", section on 'Velocardiofacial (Shprintzen) syndrome'.)

Palatal and related problems — Other findings in infants with DGS include palatal and laryngotracheal abnormalities and related feeding difficulties [3,50,51]. Palatal abnormalities include overt cleft palate and submucosal cleft palate. Velopharyngeal insufficiency in patients with DGS can be due to structural causes (eg, cleft palate) and/or neuromuscular problems (eg, hypotonia) [52]. The most common findings of velopharyngeal insufficiency are hypernasal speech and nasal regurgitation [1]. Some of these signs and symptoms are subtle and may not come to medical attention. The causes, clinical features, and diagnosis of swallowing dysfunction are reviewed in detail separately. (See "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate" and "Etiology of speech and language disorders in children", section on 'Resonance disorders' and "Aspiration due to swallowing dysfunction in children".)

Developmental and behavioral problems — Developmental delay occurs in the vast majority of patients with 22qDS, and speech delay is especially common (table 1) [1,3,4,6,37,53-57]. Intelligence ranges from normal to moderate intellectual disability. Patients typically score higher on verbal than performance measures initially, but a greater decline is seen over time in verbal domains compared with performance domains [58]. Problems in social emotional functioning and inhibition and attention disorders may occur. Deficits in motor functioning have also been reported.

Other anomalies — Patients may also present with skeletal (eg, scoliosis) and structural genitourinary tract abnormalities [1,3,50,59].

Findings in adults — Adults with 22qDS have not been extensively studied [60,61], and ascertainment bias is probably present in analyses of retrospective case series. Population-based prospective studies on adults with 22qDS are needed to better define characteristics and assist with clinical management.

In the largest retrospective series of 126 adults, 60 percent were parents of affected children, and the others were patients in craniofacial, cardiology, genetics, and psychiatry clinics [61]. Compared with a large series of children with 22qDS, adults had significantly lower rates of major cardiac anomalies (30 percent) and higher rates of palatal abnormalities (88 percent), intellectual disabilities (94 percent), and psychiatric conditions (36 percent). The most common findings were minor facial anomalies (99 percent) and hypernasal speech (picture 2). Psychiatric disorders included schizophrenia, schizoaffective disorder, and major depression. Assessment of longitudinal cognitive evaluations for 411 patients with 22qDS found that a steeper decline in cognitive function, particularly in the verbal domains (beginning around 11 years of age in one series), is associated with the development of a psychotic disorder [58]. Hypocalcemia was reported in 15 percent and ranged in severity and age of onset (birth to 33 years). Thrombocytopenia or recurrent epistaxis was observed in 12 percent of patients; both findings are noted less frequently in infants.

A prospective case-control study with 309 adults with 22qDS aimed to determine overall mortality risk [62]. Compared with their unaffected siblings, persons with 22qDS were found to have a significantly higher risk for mortality that was independently associated with global effects of 22qDS and complex congenital heart disease.

DIAGNOSIS — The diagnosis of DGS is based upon reduced numbers of CD3+ T cells, combined with either characteristic clinical findings (eg, congenital cardiac anomalies, hypocalcemia) or a demonstrated deletion in chromosome 22q11.2 (22qDS). Proposed criteria define three diagnoses: definite, probable, and possible DGS (table 3) [63]. Approximately 90 percent of patients with DGS have heterozygous deletions in chromosome 22q11.2, although this deletion is less common in those with complete DGS. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Genetic abnormalities' and 'Genetic analysis' below.)

Complete DGS is diagnosed by the presence of severe immunodeficiency (CD3+T cell numbers <50/mm3 to absent and lack of proliferation to mitogens) and athymia. A 22q11.2 deletion is identified in approximately 50 percent of patients with complete DGS [15,64]. Complete DGS is also identified on newborn screening (NBS) for severe combined immunodeficiency (SCID) that examines for the presence of T cell receptor excision circles (TRECs). (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)

TREC findings in DGS have not been systematically studied. However, excision circles were entirely absent in the few cases of complete DGS in which TREC results were reported [17,65]. Additionally, compiled data from 11 states that screen for SCID reported positive screens in infants with partial DGS [16]. Of the over three million infants screened, 78 were found to have non-SCID T cell lymphopenia and DGS/22qDS. A retrospective analysis of stored NBS blood filter cards from 48 known patients with 22qDS found abnormal TREC values in 19 percent of subjects [66]. Population-based prospective studies are necessary to determine if the infants with DGS/22qDS detected by NBS SCID have a more severe immune phenotype or if early detection results in improved clinical care/outcomes and quality of life.

NBS for genetic disorders is rapidly evolving as molecular testing improves and costs decrease. Test platforms to screen for 22qDS on NBS filter cards have been developed [67]. Discussions continue to reach consensus on population-based NBS for 22qDS and the associated ethical issues in screening for a genetic disorder with such a varied phenotype.

Evaluation in neonates — Evaluation for DGS should be considered for any neonate with a conotruncal heart lesion, hypocalcemia, and/or cleft palate.

Initial studies — Infants with suggestive signs and symptoms (table 1 and table 2) should have the following performed [1]:

Cardiac evaluation and echocardiogram (urgently)

Serum calcium and phosphorus levels

Complete blood cell count with differential to evaluate for lymphopenia

Chest radiograph to evaluate for absence of a thymic shadow (image 1)

Renal ultrasound to assess for structural genitourinary tract abnormalities

T and B cell phenotyping by flow cytometry

Immunoglobulin levels

The absence of a thymic shadow on chest imaging suggests some form of SCID, although the presence of a normal thymic shadow does not exclude DGS. Diminished thymic tissue is suggestive of an immunodeficiency. However, this is an insensitive test since stress or infection can lead to thymic involution.

Advanced studies — If the thymus appears to be small or absent, the NBS SCID screen is positive, and lymphopenia is present, further evaluation of T and B cell quantification and function should be done quickly to assure that patients with complete DGS are identified. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Immune function'.)

This evaluation should include the following studies:

In vitro T cell proliferation in response to mitogens (such as the plant lectins phytohemagglutinin [PHA] or anti-CD3 antibody). Note that proliferative responses to neoantigens (such as vaccine antigens and Candida) are not useful in neonates who have not been exposed to these agents and have a maturing immune system but can be used in older children and adults.

Analysis of TRECs is helpful for infants suspected of having complete DGS [23,68]. TREC analysis quantitates thymic output of T cells and is a more sensitive measure of thymic function than imaging of the thymus. If TREC values are low alongside low T cell counts, determination of the frequency of naïve T cells by measurement of expression of the cell surface marker CD45RA+ on CD4+ T cells helps to distinguish between complete DGS and a profound initial partial DGS presentation [68]. (See "Newborn screening for inborn errors of immunity", section on 'Overview of TREC screening test' and "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Complete DGS'.)

Flow cytometry can be used to determine T cell repertoire (T cell receptor [TCR] V-beta chain diversity), and additional analysis for recent thymic emigrants should be considered (ie, CD45RA+CD62L+ expression).

B cell function can be assessed by measuring immunoglobulin M (IgM) levels. In complete DGS, IgM is low or absent, as seen in patients with SCID. Immunoglobulin G (IgG) in neonates born after 34 weeks of gestation is of mixed maternal/infant origin, and IgA levels can be undetectable in normal infants, rising only after several months of age.

The laboratory evaluation of T and B cell function is reviewed in detail separately. (See "Laboratory evaluation of the immune system".)

Evaluation in older children and adults — The diagnosis of DGS should be considered in older children and adults with a family history of DGS and/or consistent clinical findings, including characteristic facial features, developmental/intellectual disability, conotruncal cardiac anomalies, palatal anomalies and hypernasal speech, and psychiatric problems (table 1 and table 2). Clinical manifestations in different age groups are reviewed above [61,69,70]. (See 'Clinical presentation' above and 'Findings in adults' above.)

Parameters for the initial assessment of older children and adults with 22qDS have been proposed [60]. In addition to a comprehensive medical history and physical examination, the suggested initial evaluation includes the following:

Psychiatric and cognitive assessment

Consultation with medical geneticist or genetics clinic experienced in 22qDS

Genetic analysis, such as fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), single nucleotide polymorphism (SNP) array, or comparative genomic hybridization (CGH) microarray

Complete blood cell count and differential

Endocrine studies, including measurements of thyroid-stimulating hormone, pH-corrected ionized calcium, parathyroid hormone, and serum creatinine

Abdominal ultrasound to evaluate for renal abnormalities

Echocardiogram

Genetic analysis — Genetic studies are necessary to define the molecular basis for DGS, although they are not required to make a definitive diagnosis (table 3). An appropriate initial step is to assay for a microdeletion at the critical DGS region of chromosome 22. FISH, using a probe specific for the critical deleted region in chromosome 22q11.2, was the primary test for genetic diagnosis of 22qDS (figure 1) [71].

FISH is being replaced with other more rapid and sensitive molecular test modalities including MLPA, SNP array, and CGH microarray. The last two tests offer the advantage of interrogating the entire genome rather than only the chromosome 22q11.2 region, thereby giving information about copy number variants (CNVs) in other chromosomes that can be associated with DGS-like conditions, such as 10p13.14 microdeletion syndrome or CHARGE (coloboma of the eye, heart anomalies, choanal atresia, retardation, genital and ear anomalies) syndrome secondary to microdeletions affecting chromodomain helicase DNA-binding protein 7 (CHD7) (see 'Differential diagnosis' below). Comprehensive molecular assays, such as CGH microarray, that broadly screen for CNVs are widely available and may have lower cost and faster turnaround time than FISH testing for 22q11.2 deletions, depending upon the institution or laboratory.

If testing is negative for 22q11.2 deletions, then gene sequencing of the T-box 1 transcription factor gene (TBX1) is recommended to look for disease-associated variants not detectable by the above testing. Heterozygous variants in TBX1 have been reported to cause most, if not all, features of DGS [49].

DIFFERENTIAL DIAGNOSIS — Given the complexity of the branchial-pharyngeal developmental sequence, it is not surprising that multiple genetic and teratogenic effects can result in common phenotypic outcomes.

Other congenital syndromes — Several distinct clinical syndromes share phenotypic similarities with 22qDS, including Zellweger, CHARGE (coloboma of the eye, heart anomalies, choanal atresia, retardation, genital and ear anomalies), and Opitz G/BBB syndromes [2,72].

Zellweger syndrome — Zellweger syndrome is a peroxisomal disorder that presents at birth with a typical craniofacial dysmorphism (picture 3). Unlike infants with DGS, those with Zellweger syndrome typically have hepatomegaly that is associated with cirrhosis and biliary dysgenesis. (See "Peroxisomal disorders".)

CHARGE syndrome — Infants with the CHARGE association share phenotypic features with patients with 22qDS, including cardiac defects, cleft palate, and hearing loss [73-75]. CHARGE is distinguished from DGS, however, by coloboma, choanal atresia, genital anomalies, and lack of 22q11.2 deletion.

One report described a patient with CHARGE syndrome and profound T cell lymphopenia [76]. A genetic variant in the CHD7 gene was identified in this patient. A pathogenic variant in CHD7 is found in approximately 70 percent of patients fulfilling the criteria for CHARGE, and this report provided the first link between CHD7 variants and T cell lymphopenia. Subsequently, five patients were described with CHD7 pathogenic variants and a complete DGS phenotype (T-B+NK+ severe combined immunodeficiency [SCID] and Omenn syndrome) [77,78]. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)

A retrospective analysis of 25 patients with CHARGE association and confirmed CHD7 pathogenic variants described a spectrum of immunodeficiencies in the majority of this cohort [79]. The incidence of lymphopenia was higher in the CHARGE association cohort compared with the 22q11.2 cohort, suggesting that immunologists should be part of the treatment team for CHARGE association patients.

Opitz G/BBB syndrome — The Opitz G/BBB syndrome is characterized by ocular hypertelorism, asymmetry of the skull, hypospadias, and laryngoesophageal defects [80]. These features distinguish Opitz G/BBB from DGS. The genetic basis for Opitz G/BBB remains poorly characterized. However, several patients have been described with 22q11.2 microdeletions [81]. More sensitive genetic analysis in one patient with Opitz-like syndrome phenotype and 22q11.2 microdeletion demonstrated that this patient shared the same deletions as patients with DGS [82]. (See "Causes of primary adrenal insufficiency in children", section on 'Disorders of steroidogenesis'.)

Severe combined immunodeficiency — Various forms of SCID (eg, Omenn syndrome, SCID with maternal T cell engraftment) should be excluded in patients with suspected atypical complete DGS since immune corrective therapies (thymic tissue implantation versus hematopoietic cell transplantation) and favorable outcomes vary greatly. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)

Teratogen exposure — Phenotypically similar patients have been described secondary to several in utero exposures, such as isotretinoin or ethanol, or maternal conditions, such as diabetes [72,83]. In these cases, genetic abnormalities have not been identified, and the phenotypic similarities are presumably a result of teratogen exposure at key developmental periods of neural crest cell migration.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Typical genotype and phenotype – Most cases of DiGeorge syndrome (DGS) are caused by a 22q11.2 deletion. The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia, although the phenotype is variable (table 1 and table 2). Palatal abnormalities and developmental delay are common. (See 'Introduction' above and 'Clinical presentation' above.)

Immunodeficiency – Immunodeficiency is common in patients with DGS and can range from recurrent sinopulmonary infections (partial DGS) to congenital athymia with severe combined immunodeficiency (SCID) like phenotype (complete DGS). In general, the severity of the immunodeficiency is related to the degree of thymic hypoplasia. (See 'Immunodeficiency' above.)

Additional clinical features – Other features of DGS that present outside of infancy and into adulthood include recurrent infections, autoimmunity, developmental delay, psychiatric abnormalities, and chronic inflammatory diseases (table 1). (See 'Clinical presentation' above and 'Findings in adults' above.)

Evaluation in neonates – The diagnosis of and evaluation for DGS should occur for any neonate with a conotruncal heart lesion, hypocalcemia, and/or cleft palate. This evaluation should proceed urgently since clinical manifestations in the neonate can be life threatening in the short term. (See 'Evaluation in neonates' above.)

Evaluation in children and adults – The diagnosis should be considered in older children and adults with a family history of DGS or consistent clinical findings (table 1 and table 2). (See 'Evaluation in older children and adults' above.)

Diagnosis – The diagnosis of DGS is based upon reduced numbers of CD3+ T cells, combined with either characteristic clinical findings or a demonstrated deletion in chromosome 22q11.2 (table 3). Criteria have been proposed for definite, probable, and possible DGS. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis includes exposure to teratogens and other congenital syndromes with similar clinical features. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 83396 Version 17.0

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