DiGeorge Syndrome

22q11.2DS (DiGeorge syndrome, or DGS) has a wide range of clinical features, including the following:

• Abnormal facies

• Congenital heart defects

• Hypoparathyroidism with hypocalcemia

• Cognitive, behavioral, and psychiatric problems

• Increased susceptibility to infections due to thymic aplasia or hypoplasia

Some collectively refer to these by the acronym CATCH-22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia resulting from 22q11.2 deletion). This designation has not been in use recently. See the image below. (See DDx and Workup.)

Mother and children with 22q11.2 deletion syndrome.

22q11.2DS encompasses the following phenotypically similar disorders—including DiGeorge syndrome:

• Velocardiofacial syndrome (VCFS, or Shprintzen syndrome)

• Cayler cardiofacial syndrome (asymmetric crying facies)

• Conotruncal anomaly face (CTAF) syndrome

• Some cases of autosomal dominant Opitz G/BBB syndrome

These syndromes were described as separate entities based on their prominent features and named as such prior to the discovery that they shared a common microdeletion of the DGS critical region, on chromosome 22 at band 22q11.2.

DiGeorge syndrome was originally described as a developmental field defect in the third and fourth branchial pouches, often presenting in the neonatal period with hypocalcemia and severe immune deficiency. Later, conotruncal heart defects were included. Velocardiofacial syndrome, on the other hand, was initially recognized as a syndrome of palatal defects, conotruncal heart defects, and characteristic facial features. (See Pathophysiology and Etiology.)

Partial versus complete 22q11.2DS based on immunologic features

Thymic hypoplasia or aplasia leading to defective T-cell function is one of the main features of 22q11.2DS. Depending on the T-cell proliferative responses to mitogens, the immunologic features of 22q11.2DS can be classified as partial or complete. Patients with partial 22q11.2DS have a below-normal proliferative response to mitogens, and the immune parameters may improve with time. Interleukin (IL)–7 may play a critical role in T-cell homeostasis in patients with partial 22q11.2DS.[4] However, in subjects with thymic hypoplasia, despite compensatory increase of T-cell numbers, TCR repertoire is reported to be decreased than normal controls.

Patients with complete 22q11.2DS are rare and have no T-cell responses to mitogens. These patients usually have very few detectable T cells in peripheral blood (1-2%) and usually require treatment of thymic transplant or hematopoietic stem cell transplantation. (See Treatment and Medication.)

B-cell defects

Although 22q11.2DS is categorized as a T-lymphocyte immunodeficiency, B-lymphocyte defects also occur. A review of 1023 patients with DGS revealed that 6% of patients older than 3 years had hypogammaglobulinemia and that 3% of patients with DGS were receiving immunoglobulin replacement therapy.[5]  

The 22q11.2 deletion results in a range of embryonic developmental disruptions involving the head, neck, brain, skeleton, and kidneys. Portions of the heart, head and neck, thymus, and parathyroids derive from the third and fourth pharyngeal pouches, and this developmental field is disrupted due to the chromosomal microdeletion. This, in turn, leads to hypocalcemia, variable T-cell deficiency, and cardiac outflow defects. A combined T- and B-cell deficiency in part results from lack of T-helper cell function as typically seen in cases of complete 22q11.2DS.

Disease mechanism

The syndrome is caused by a microdeletion of band 22q11.2. The long arm of chromosome 22 (at q11) is prone to a microdeletion because of the presence of eight nonallelic, flanking, low-copy repeat DNA (deoxyribonucleic acid) sequence clusters (LCR22) labeled A–H. Clusters A–D are near the centromere. These repeat sequences lead to meiotic nonallelic crossing over between the 2 copies of chromosome 22 during spermatogenesis or oogenesis.

The most common deletion present in 85% of individuals is 3 million base pair (Mb) in size, extends from A to D, and encompasses approximately 40 genes and 4 micro RNAs. Among them is the TBX1 gene, suspected to play a major role in many of the typical features of this syndrome. There is some evidence that suggests that CNVs (copy number variants) and microRNAs in the rest of the genome likely influence the clinical variability seen even among the patients having the common deletion.[6]  The remaining 15% of affected individuals have atypical smaller deletions including any of the LCR22 D–H.

Among other genes mapped in the deleted region that have been implicated in the pathogenesis of 22q11.2DS include HIRA (a transcriptional corepressor of cell cycle–dependent histone gene transcription and mammalian homologue of the yeast Hir1p and Hir2p proteins) and UFD1L (homologue of a highly conserved yeast gene involved in the degradation of ubiquitinated proteins).

Disease mechanism of immunodeficiency

The characteristic immunodeficiency in 22q11.2DS is a mild to moderate defect in T-cell lineage caused by thymic hypoplasia, typical of incomplete DGS. Naïve T-cell production is usually reduced with resultant low TREC (T-cell receptor excision circles) detected by PCR. Only a small fraction of patients present with marked impairment of T-cell function associated with a complete absence of thymus/T-cells (complete DGS), and severe systemic infections, consistent with severe combined immunodeficiency phenotype. Such patients can be detected by Newborn SCID Screening in the states where TREC enumeration is included in the newborn screening. Improvement with age in T-cell functions and numbers may be attributed to homeostatic T-cell proliferation secondary to limited T-cell production.

Variable secondary humoral defects, including hypogammaglobulinemia and selective antibody deficiency, may be present. This is attributed to impaired T-cell help, and su sequent impaired terminal B-cell maturation.

Disease mechanism of autoimmune diseases

Impaired T-cell production may predispose patients with 22q11.2 deletion to autoimmune diseases. In a cohort of 195 patients with 22q11.2DS, various autoimmune diseases, including juvenile rheumatoid arthritis, idiopathic thrombocytopenic purpura, and autoimmune hemolytic anemia, were more prevalent than in the age-matched general population.[7] No specific pattern of autoimmune disease appears to be associated with 22q11.2 deletion.

The frequency of autoimmune disorders in patients with partial 22q11.2DS was reviewed by Tison et al[8] in a large cohort of pediatric patients, and in that review, cytopenias and hypothyroidism were reported to be the most common autoimmune conditions. Autoimmunity was found in 10 (8.5%) of 130 patients, a frequency similar to that seen in a previous study in a different institution. Children with high or normal naive CD4 T-cell counts early in childhood had a lower risk of autoimmune disease.

Association with Graves disease has been reported sporadically.[9, 10] Other associated diseases include immune cytopenias,[11] immune thrombocytopenic purpura,[12] juvenile rheumatoid arthritis–like polyarthritis,[13] autoimmune uveitis,[14] and severe eczema.[15]

DiGeorge syndrome and velocardiofacial syndrome (VCFS) have also been found to be significantly associated with asthma but not with allergic rhinitis.[16]

A higher frequency of autoimmune diseases in 22q11.2DS patients is partly attributed to suppressed expression of AIRE (autoimmune regulator) in the thymic epithelial cell due to thymic hypolasia (low T-cell numbers), resulting in suppressed negative selection of autoreactive T cells in the thymus.

Disease mechanisms of neuropsychiatric disorders

The 22q11.2 microdeletion is the strong known genetic risk factor for schizophrenia and has been implicated with microRNA (miRNA)-mediated dysregulation. Two candidate genes for this condition are DiGeorge syndrome critical region gene 8 (DGCR8), which encodes a component of the microprocessor complex essential for miRNA biogenesis and miR-185.[17] miR-185 is reported to be down-regulated in brains of patients with idiopathic schizophrenia, and also is reported to be down-regulated in patients with 22q11.2 DiGeorge syndrome.[18]

Mode of inheritance

The occurrence of 22q11.2DS is sporadic in more than 90% of cases, being the result of de novo (noninherited) deletions. About 10% have inherited the deletion from a parent as an autosomal dominant condition. Sibling involvement has been observed only if a chromosome 22 deletion has been found in a parent. The hereditary cases show no predilection in inheritance from the mother or father, and an affected person has a 50% chance of transmitting the condition to his or her child. Wide intrafamily and interfamily variability in clinical manifestations is seen.

Estimates of the incidence of 22q11.2DS range from 1 per 4000 to 1 per 7000 births.[19, 20] These estimates are based on a few population-based screening studies done in the 1990s and early 2000s and the diagnoses based on FISH technology. Thus, smaller deletions would have been missed. True prevalence can only be determined by uniform newborn screening.

Although 22q11.2DS is a congenital condition, the age at diagnosis is variable, being largely dependent on the severity and the types of associated birth defects. Thus, patients with more serious congenital cardiac defects or hypocalcemia are likely to be diagnosed in the neonatal period whereas those with only a submucous cleft palate and delayed speech, mild cardiac defects, normal immune function, or minimal facial anomalies are detected much later in childhood. Recurrent infections usually present in patients older than 3-6 months.

Late diagnosis into adulthood continues to be reported, especially in persons with isolated mild symptoms. Prenatal diagnosis in fetuses with a congenital heart anomaly has been made frequently and should be offered to a pregnant woman at risk of carrying a fetus with this syndrome.

The prognosis for 22q11.2DS varies widely, depending largely on the nature and degree of involvement of different organs, and it is important to note that many adults do live long and productive lives.

The most common cause of mortality in 22q11.2DS is a congenital heart defect and the second most common is severe immune deficiency. Mortality is higher in infancy because of the severity of these 2 conditions. Infants with thymus aplasia present with severe immunodeficiency and typically die of sepsis, caused by either bacterial or fungal infections.

In a large European collaborative study, 558 patients with 22q11.2DS were evaluated using a questionnaire.[21] Eight percent of the patients died, with more than half of the deaths occurring within the first month of life and the majority happening within 6 months of birth. Of the patients who survived, 62% had only mild learning problems or were developmentally normal. All the deaths except one were attributable to congenital heart disease. In this study, only 11% of patients were older than 18 years. Adult mortality data are limited. In one study, researchers compared survival of 102 adults (>17 yrs) with 22q11.2DS to survial of their 162 unaffected siblings. The study found survival in the affected group was reduced with an average age of death of 41.5 years (47.3 years in those without major congenital heart disease).[22]

Genetic counseling is essential to educate parents regarding the recurrence risk of 22q11.2DS. In addition, the families of patients with clinically significant immunodeficiency should be educated regarding the potential complications from exposure to live-attenuated vaccines that include rotavirus, MMR, and chicken pox vaccines.

Patients' families often feel alone after the syndrome is diagnosed. Because of its rarity, most parents have neither heard of this disorder nor do they know anyone who has it to whom they can turn to for support. Support groups and other resources are of invaluable help in this regard. Many written educational materials are available through various organizations, including those listed below.

International 22q11.2 Deletion Syndrome Foundation, Inc

PO Box 532

Matawan, NJ 07747USA

Telephone: 877-739-1849; email: info@22q.org

www.22q.org

Max Appeal

15 Meriden Ave

Stourbridge, West Midlands; DY8 4QN United Kingdom

Telephone: 0300-999-2211

www.maxappeal.org.uk

National Library of Medicine Genetics Home Reference: 22q11.2 deletion syndrome

National Center for Biotechnology Information (NCBI) Genes and Disease: DiGeorge syndrome

Velo-Cardio-Facial Syndrome Education Foundation, Inc

PO Box 12591

Dallas, TX 75225, USA

Telephone 1-855-800-8237); email: info@vcfsef.org

www.vcfsef.org

Chromosome 22 Central

108 Partinwood Drive

Fuquay-Varina, NC 27526, USA

Telephone: 919-567-8167; email: usinfo@c22c.org

www.c22c.org

The most common reason to suspect 22q11.2DS (chromosome 22q11.2 deletion syndrome; DiGeorge syndrome [DGS]) is a cardiac anomaly, especially a conotruncal one. Neonatal hypocalcemia should also raise suspicion for this syndrome, especially if the hypocalcemia or heart defect is coupled with cleft palate. A picture of severe immune deficiency with low T-cell  numbers as compared to age-appropriate controls in early infancy should raise the suspicion of this syndrome as well.

The characteristic facies of this syndrome often are subtle in infancy and not fully manifested until the child is older; therefore, they are not a common indication for a genetic investigation. The distinctive facial features may even be absent or more subtle in people of African-American or in others of nonwhite descent.

Developmental delay may be mild in infancy or may go unnoticed until the child reaches school age. Additional abnormalities of every organ system have been reported,[23] although individually they are rare. Details of the common symptoms/anomalies are described below.

A history of maternal diabetes and/or exposure prenatally to alcohol and other drugs like isotretinoins is relevant because of the overlapping phenotypes associated with fetal alcohol syndrome, diabetic embryopathy, and isotretinoin embryopathy.

Craniofacial features

Characteristic facies of 22q11.2DS are easier to recognize in white children; they consist of a high and broad nasal bridge, long face, narrow palpebral fissures, and micrognathia. Microcephaly, a dimple on the nose, and asymmetrical crying face may be present. Facial features become more pronounced as the children grow into the second decade.

Overall, about 69% of cases have palatal abnormalities. A hypernasal voice indicates velopharyngeal incompetence (VPI). VPI may be due to submucous cleft palate and is more common than an overt cleft of the secondary palate. The presence of an overt cleft palate improves the chances of an earlier diagnosis. There may be a bifid uvula. Rarely, cleft lip and cleft palate occur together. Recurrent episodes of otitis media may be observed. Conductive and/or sensorineural hearing loss may be present. Craniosynostosis occurs on rare occasions.

Immune disorders and recurrent infections

The overall incidence of immune dysfunction in 22q11.2DS is 77%.[23]

However, infections as the first manifestation is unusual, but rather, cardiac malformations and hypocalcemia are the first signs in the neonatal period. Recurrent infections are a major problem and an important cause of later mortality.

Increased susceptibility to infections caused by organisms typically associated with T-cell dysfunction is observed. These include systemic fungal infections, Pneumocystis (carinii) jiroveci infection, other bacterial infections, and disseminated viral infections.[24, 25]

Autoimmune disease such as autoimmune cytopenia, thrombocytopenia, and juvenile rheumatoid arthritis are most common. Autoimmune thyroid disease, autoimmune uveitis, and selective IgA deficiency may occur as well. Atopic disorders of severe eczema[26] and asthma are also seen.

Feeding difficulties

Significant feeding difficulties are present in about 36% of patients. These may be due to poor sucking and nasal regurgitation due to VPI or a submucous cleft palate. The swallowing problem usually resolves by the end of the first year, leaving the child with hypernasal speech as the major remaining manifestation. Abnormal swallowing, with or without aspiration, may occur due to dysmotility and abnormality of the oropharyngeal and cricoesophageal swallowing phase.

Developmental delay/learning difficulties

Developmental delay and learning difficulties are observed in 70-90% of patients with 22q11.2DS. In infancy, developmental milestones are achieved later than expected for age. Delayed language acquisition is often seen in older children.

A frequent pattern of disability is observed,[27] consisting of a low performance on intelligence quotient (IQ) testing compared with verbal IQ, which creates problems with nonverbal learning, abstract reasoning, and math. In school-aged children, full-scale IQ scores can range from average to low average to mild mental retardation. The incidence of mild mental retardation is approximately 30%. Brain anomalies like polymicrogyria and enlarged Sylvian fissures have rarely been noted.[28]

Behavioral and neuropsychiatric problems

Behavioral and psychiatric problems may be observed in patients with 22q11.2DS.[29, 30] Children and adults have high rates of behavioral, psychiatric, and communication disorders. In children, these include attention-deficit/hyperactivity disorder, anxiety, autism spectrum disorder, and affective disorders. Bipolar disorder, autistic spectrum disorder, schizophrenia, and schizoaffective disorder are reported in 10-30% of teenagers and adults with the syndrome.[28, 31]  Increased risk for early onset Parkinson disease (younger than 50 years of age) is observed.[32]

Endocrinologic conditions

Main problems are with parathyroid deficiency[33] :

• Hypocalcemia

• Nephrocalcinosis

• Tetany: Neonatal tetany has been reported as a result of hypocalcemia.

Hypocalcemia due to hypoparathyroidism can cause seizures. The incidence of hypocalcemia varies widely, from 17-60%.[34] This is frequently a self-limiting problem, and by age 1 year approximately 50% of patients no longer need calcium supplementation.

Additional endocrine manifestations include hypothyroidism in children and ∼20% of adults, and hyperthyroidism in children.[35] Rarely, growth hormone deficiency has occurred.

Other associated conditions

Other associated conditions include the following:

• Kidney and renal pelvis duplications

• Growth retardation

• Neurologic abnormalities: May include structural brain abnormality and seizures

• Genitourinary malformation

• Rash and lymphadenopathy[36]

• Abnormal lung lobation

• Malignancies like hepatoblastoma, renal cell carcinoma, and Wilms tumor[37]

There is considerable variability in individual physical findings and in the organ systems that may be involved in 22q11.2DS (chromosome 22q11.2 deletion syndrome; DiGeorge syndrome [DGS]).

Patients usually have characteristic facial features, which become more pronounced as the child grows into the second decade. These are more commonly and easily recognized in white children. Common features include the following (see the images below)[1] :

• Retrognathia or micrognathia

• Long face

• High and broad nasal bridge

• Narrow palpebral fissures

• Small teeth

• Asymmetrical crying face

• Downturned mouth

• Short philtrum

• Low-set, malformed ears

• Hypertelorism

  Mother and children with 22q11.2 deletion syndrome.

  An African American girl with 22q11.2 deletion syndrome.

  The same child as in the previous image, showing an asymmetrical crying face.

Although VPI is more common, a cleft of the soft palate or a bifid uvula (associated with a submucous cleft palate) may be present. The voice can be hypernasal.[38]

Hypodevelopment of the lingual cusp of the mandibular first premolars and enamel opacities may also exist.[39]

Ocular findings

Ocular features of 22q11.2DS include the following:

• Posterior embryotoxon

• Tortuous retinal vessels

• Eyelid hooding

• Strabismus

• Ptosis

• Amblyopia[40]

• Familial exudative vitreoretinopathy[41]

• Sclerocornea[42]

Skeletal findings

Skeletal features of 22q11.2DS include the following:

• Limb abnormalities: Ectrodactyly, polydactyly and long, tapering fingers[43]

• Craniosynostosis

• Scoliosis: With or without vertebral anomalies

Patients may have short stature; a decrease in the rate of linear growth may suggest a rarely seen growth hormone deficiency.

Pulmonary conditions

Pulmonary features of 22q11.2DS include the following:

• Tracheoesophageal fistula

• Short trachea with a reduced number of tracheal rings

• Abnormal thyroid cartilage

• Laryngomalacia

• Tracheomalacia

• Bronchomalacia

• Congenital anterior glottic web[3]

Cardiac and GI findings

Heart murmur and other cardiac findings would suggest a congenital heart defect. Congenital heart defects are observed in 74-80% of patients. A higher incidence is noted in cases diagnosed during infancy because of the symptomatic nature of the heart lesion. Any conotruncal heart defect can occur. In infancy, tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch are more common; whereas ventricular septal defect (VSD), pulmonary atresia plus VSD, and other conotruncal defects are seen in cases diagnosed after age 2 years. Rare cardiac anomalies in 22q11.2DS include the following:

• Vascular ring anomaly

• Transposition of the great arteries with VSD

• Coarctation of the aorta

• Atrial septal defect (ASD)

• Pulmonary stenosis

• Hypoplastic left heart

• Patent ductus arteriosus.

Anomalies of the carotid arteries should be checked for patients needing pharyngeal surgery.

GI anomalies, such as esophageal atresia and anal atresia or stenosis, intestinal malrotation, tracheoesophageal fistula, have all been reported.

As described in the initial section, autoimmune complications are common in 22q11.2DS patients, although autoimmune conditions are not typically seen at initial presentation in infants or young children.

Laboratory studies used in the evaluation of 22q11.2DS include the array comparative genomic hybridization (aCGH), fluorescent in situ hybridization (FISH), TBX1 gene sequencing or TBX1 deletion/duplication analysis, and multiplex ligation-dependent probe amplification (MLPA).

Array comparative genomic hybridization (aCGH) is the preferable and most appropriate test for detecting the 22q11.2 deletion. It has the added benefit of detecting large or submicroscopic chromosomal deletions/duplications on all chromosomes in addition to the classic chromosome 22q11.2 deletion. It may also provide refinements of the breakpoints, although the size of the deletion has not yet shown any clinical correlation.[44]

Fluorescent in situ hybridization (FISH) is readily available with chromosome analysis but smaller deletions may not be detectable. If aCGH is unaffordable/unavailable, a FISH study for the 22q11.2 deletion with a karyotype should be requested. The karyotype detects chromosome rearrangements and other chromosomal abnormalities.

Request TBX1 gene sequencing or TBX1 deletion/duplication analysis when aCGH does not show a deletion yet the syndrome is clinically suspected. This should be performed after consultation with a clinical geneticist.

Multiplex ligation-dependent probe amplification (MLPA) appears to be equivalent to the FISH technique[45] and can be used for rapid diagnosis when the syndrome is suspected clinically or for confirmation of the deletion after aCGH analysis. Additionally, an MLPA analysis has been designed to be performed on DNA extracted from dried blood spot samples obtained from Guthrie cards collected via the newborn screening program.[46]

Other means of diagnosis are being evaluated, including a rapid polymerase chain reaction (PCR) assay–based method.

Indications for 22q11.2DS screening depend on the clinical picture. The 22q11.2 deletion occurs in 20-30% of newborns with isolated conotruncal cardiac malformations. Therefore, screening all newborns with conotruncal anomalies for 22q11.2 deletions is well justified. Some other candidates for screening are neonatal hypocalcemia (74%), interrupted aortic arch (50-60%), and velopharyngeal insufficiency (64%). Only about 1% of cases with any cardiac lesion detected later in life and 0-6% of cases of isolated schizophrenia (0-6%) may have 22q11.2DS, thus these facts may warrant an evaluation by a clinical geneticist for advice regarding screening for 22q11.2DS.

The signs and symptoms suggesting 22q11.2DS also depend on the patient’s age at evaluation. Generally, however, 2 or more of the following clinical findings should prompt a laboratory confirmation of the diagnosis:

• Conotruncal heart anomalies

• Palatal defects

• Hypernasal speech

• Nasopharyngeal reflux

• Developmental/learning disabilities

• Behavioral/psychiatric problems

• Immunodeficiency

• Hypocalcemia

• Typical facial features

CBC count

A CBC with an elevated mean platelet volume above 10 fL may be a useful screening test involving no extra laboratory work, cost, or patient discomfort. Authors of a retrospective study suggested that the platelet finding may help the clinician to rapidly decide whether to order irradiated blood products to prevent potentially fatal transfusion-associated graft versus host disease in case of severe immune deficiency and may alert clinicians to monitor serum calcium levels closely to prevent hypocalcemic seizures.[47]

Calcium and parathyroid hormone studies

Hypocalcemia may occur in 22q11.2DS (chromosome 22q11.2 deletion syndrome; DiGeorge syndrome [DGS]) secondary to hypoparathyroidism. Measure the ionized serum calcium level to evaluate parathyroid function. If the level is low, obtain simultaneous ionized serum calcium and parathyroid hormone levels. Consult an endocrinologist. Latent or subclinical hypoparathyroidism can be unmasked by performing a diagnostic ethylenediaminetetraacetic acid (EDTA) challenge test. Despite occasional normal calcium and parathyroid hormone levels, the secretory reserve for parathyroid hormone is usually diminished in patients with 22q11.2DS.

Dilated retinal examination

A dilated retinal examination can help to detect familial exudative vitreoretinopathy.[41]

Perform an absolute lymphocyte count in the peripheral blood. If lymphopenia is present, consult an immunologist and obtain T- and B-cell counts.

Note that a normal-sized thymus does not necessarily ensure normal T-cell development, and patients with a very small thymus, even in an ectopic location, may have T-cell responses to mitogens that range from below normal to normal. Mitogen responsiveness may be the most important parameter in assessing T-cell function, and peripheral T-cell numbers may not be indicative of T-cell responses.

In other words, although a finding of very low to absent T cells in the peripheral blood suggests severe immunodeficiency, decisions regarding treatment should be based on T-cell proliferative responses to antigens and mitogens, not on the number of T cells.

Newborn screening of severe combined immunodeficiency (SCID), which detects TREC levels in dried blood spots, is likely to identify 22q11.2DS as decreased TREC levels. Newbon screening of SCID may facilitate diagnosis of this condition at an earlier age.

Flow cytometry

Flow cytometry is performed in vitro to estimate the number of T cells in peripheral blood and their proliferative responses to mitogens and antigens. Flow cytometry studies measuring CD45RA+ T and CD45RO+ cells should also be performed, to distinguish patients with complete DiGeorge syndrome from patients with the more common partial DiGeorge syndrome.[48]

Advances in multicolor flow cytometry, noninvasive imaging techniques, and molecular assessments of thymic function have enabled a more comprehensive characterization of human thymic output in clinical settings than in the past. These techniques have been particularly valuable in monitoring reconstitution of T cells after therapeutic thymic grafting for complete 21q11.2 DS

RT PCR assay

T-cell receptor excision circles (TRECs) are small episomal pieces of DNA formed during the rearrangement of T-cell receptor genes of thymocytes undergoing differentiation in the thymus.

The use of real-time, quantitative reverse transcriptase (RT) PCR methods for TREC quantification provides a novel tool for estimating recent thymic function in different clinical situations, including in patients with 22q11.2DS and in persons undergoing thymic transplantation.

In newborn screening, the TREC assay is performed on DNA isolated from the Guthrie card blood spots. Decreased TRECs as a measure of decreased thymopoiesis are seen in infants with congenital T-cell defects, such as SCID, idiopathic T lymphopenia, ataxia telangiectasia, as well as 22q11.2DS. However, very mild form of 22q11.2DS with little thymic hypoplasia may not be detected with this screening measure.

Antibody response

At times, a sudden increase in CD3+/CD4+ T cells is observed in patients with DGS and is associated with a modest mitogen response but no proliferative response to antigens. Response to antigens is the best predictor of the ability of the T cells to protect against infection and is the most clinically relevant of the in vitro tests of T-cell function.

Evaluation of humoral immunity reveals variable immunoglobulin levels and depends on the extent of T-cell deficiency. As would be expected (ie, because normal B-cell development requires normal T-cell function), the B-cell repertoire is normal in patients whose only measurable T-cell defect is a low number. Patients with partial DGS generate good antibody response to protein vaccines, but no data are available on polysaccharide vaccines. Increased prevalence of immunoglobulin A deficiency was observed in 4 of 32 patients with 22q11.2 deletion.

Radiography and MRI

Perform chest radiography and other imaging studies based on the cardiologist's recommendations. Chest radiography can reveal a decreased thymic silhouette but is unreliable for thymus assessment. Magnetic resonance imaging (MRI) is slightly better; however, thymic size evaluation is not recommended, because it is a poor predictor of immune function.

Radiography of the head may reveal CNS calcifications, while radiography of the abdomen can depict nephrocalcinosis; however, routine radiography of these structures is unnecessary.

CT scanning

Although computed tomography (CT) scanning of the thorax and angiography in patients with 22q11.2DS may show the following, echocardiography is preferred to CT scanning to avoid radiation:

• Malformations of the heart and great vessels

• Interrupted aortic arch

• Tetralogy of Fallot

• Truncus arteriosus

CT scanning of the neck in patients with 22q11.2DS may show lower carotid artery bifurcations and thyroid abnormalities, including the absence of a lobe, absence of isthmus, and retrocarotid or retroesophageal extension,[49] but usually is unnecessary. MR angiography of the neck is preferable if surgery is planned on the neck.

An absent thymus or one in an aberrant location may be noted on chest radiographs and CT scans. However, despite the emphasis on thymic defects in the literature about DGS, they are clinically significant in less than 5% of cases. Maldescent of the thymus is extremely common. Therefore, CT scanning of the neck and chest is not routinely recommended.

Echocardiography

The range of cardiovascular anomalies in chromosome 22q11.2DS is wide, although conotruncal defects are the most frequent ones. Because slight variations in a defect may dictate which surgical intervention is used, 2-dimensional (2-D) and color Doppler echocardiography are essential to define the anatomy. The thymus may also be visualized in this way. (Although cardiac catheterization may not be needed, it can provide helpful information in some situations.)

Angiography

Either magnetic resonance angiography (MRA) or conventional angiography is necessary to identify abnormalities of the internal carotid arteries before neck surgery is performed.

Prenatal diagnostic testing for chromosome 22q11.2DS can be offered to at-risk couples.[50, 51] Indications for such testing include a previous child or a parent with the syndrome or the in utero detection of a conotruncal cardiac defect.[52] Any of the following are selected based on the clinical situation:

• FISH using commercial probes: The most common technique used to detect 22q11.2 deletion[53] ; chromosomal breakpoints and deletion size are determined by short tandem repeat tests or further FISH probes[53]

• FastFISH: A rapid FISH method that allows the release of accurate results the same day that amniocentesis is performed[54]

• Multiplex ligation-dependent probe amplification (MLPA) single-tube assay: Detects the 22q11.2 region and other chromosomal regions associated with DGS; the advantage of MLPA is that it is a rapid, reliable, economical high-throughput test[53, 45]

• High-resolution single-nucleotide polymorphism (SNP) genotyping assay[55]

• Chromosomal microarray analysis (CMA): A high-resolution genome scanning procedure for DNA dosage aberrations; it can detect single copy number aberrations

In a skin biopsy study, Selim et al concluded that dyskeratotic keratinocytes, satellite cell necrosis, and parakeratotic scale with neutrophils characterize the cutaneous rash seen in patients with a form of complete DGS known as atypical complete DGS. Thus, according to the report, these lesions in patients with DGS should indicate to a pathologist that this relatively rare form of the syndrome may be present.[56] Thymic biopsy findings in DGS are essentially normal except for evidence of hypoplasia.

A multidisciplinary team best cares for individuals with 22q11.2DS; however, one physician (usually the primary physician) must take the lead and provide a medical home for the patient. The primary physician also must monitor growth and development. A system-by-system approach results in the best outcome.

Management of 22q11.2DS includes the following:

• Calcium supplementation: For hypoparathyroidism-associated hypocalcemia; vitamin D supplementation may also be needed

• Surgery: Cardiovascular surgery, cleft palate repair, and, for congenital anterior glottic webs, tracheotomy or surgical reconstruction

• Immunodeficiency: Therapies include thymus transplantation (allogeneic processed thymus tissue [Rethymic]) and adoptive transfer of mature T cells (ATMTC) for individuals with complete DiGeorge syndrome and appropriate prophylaxis measures and monitoring autoimmune complications for incomplete or partial DiGeorge syndrome.

Helpful clinical guideline summaries include those from the Joint Council of Allergy, Asthma and Immunology (Practice parameter for the diagnosis and management of primary immunodeficiency[57] ) and the British Committee for Standards in Haematology ([1] Transfusion guidelines for neonates and older children; [2] amendments and corrections to the transfusion guidelines for neonates and older children[58] ).

Contraception

For patients with chromosome 22q11.2 deletion syndrome, gynecologic evaluation and contraceptive education should be instituted at age 12-18 years and after age 18 years.

Follow-up

Consensus guidelines for follow-up finalized in 2010 at the International 22q11.2 Deletion Syndrome Meeting[59] for use by the international community are an excellent resource. Practical guidelines for managing problems in adults with 22q11.2 DS were published in 2015 and are very useful as well.[60] A good source for professionals is the 22q11.2 society (22qsociety.org), which consists of a group of researchers and physcians who specialize in this syndrome.

The utmost care must be taken to avoid the use of nonirradiated blood products in patients with 22q11.2DS. In the presence of significant T-cell defects, transfusions with nonirradiated blood may prove fatal secondary to a graft versus host response initiated by donor lymphocytes contaminated in blood products. If a blood transfusion is necessary in infancy, use only cytomegalovirus-negative, irradiated blood products.

Do a complete blood count (CBC) at diagnosis and again at age 1-5 years. If absolute lymphopenia is present, consult an immunologist. Follow the immunologist's recommendations regarding follow-up for future immunologic issues and for immunizations.

Live vaccines are typically contraindicated in patients with 22q11.2DS and in household members of such patients because of the risk of shedding of live organisms. Adverse events and fatal reactions have been well documented after severely immunocompromised patients with 22q11.2DS have received live vaccines[61] ; however, a few studies have shown that live viral vaccines (LVVs) may be safe in select populations affected by the syndrome.

Azzari et al evaluated the safety and immunogenicity of measles-mumps-rubella (MMR) vaccine in children with DGS and found no severe adverse reactions in the 14 patients studied.[62] Patients and control subjects experienced the same frequency of seroconversion for measles and rubella. The mean titers of anti-measles or anti-rubella antibodies were the same in patients and controls, and no decrease in CD4 cells was detected after immunization.

In a study of 53 patients at Texas Children’s Hospital with partial 22q11.2DS, no significant adverse events were recorded in the 25 who received an LVV.[63]

Similarly, a retrospective analysis by Perez et al of 59 patients with 22q11.2DS who received LVV for varicella (32 patients) and MMR (52 patients) found that the incidence of adverse effects was comparable to that reported in the general population. All of the side effects were mild.[64]

Obtain a serum calcium level at diagnosis and repeat at ages 1-5, 6-11, 12-18, and over 18 years. If the patient is found to be hypocalcemic, begin calcium supplementation after proper tests (simultaneous serum calcium and serum parathyroid hormone [PTH] levels) are performed. Vitamin D supplementation may become necessary.

A study by Matarazzo et al indicated that in children with syndromic hypoparathyroidism, subcutaneous recombinant human PTH (rhPTH) therapy used in place of calcium and vitamin D supplementation can effectively treat hypocalcemia while sparing patients the side effects of calcium and vitamin D. In this 2.5-year, self-controlled trial, involving 6 pediatric patients (including 2 with DiGeorge syndrome), rhPTH therapy enabled 2 patients to end treatment with calcium and vitamin D, 3 patients to stop calcium therapy, and 2 patients to reduce vitamin D treatment. In 4 of the patients, fewer tetanic episodes occurred during rhPTH treatment than during conventional therapy.[65]

The FDA approved the first therapy, allogeneic processed thymus tissue (Rethymic), to reconstitute immunity in children with congenital athymia in October 2021. 

Several therapies have been used to treat immunodeficiency associated with 22q11.2DS. Cases of immune reconstitution have been reported following transplantation of human leukocyte antigen (HLA) ̶ identical bone marrow, peripheral blood mononuclear cells, and fetal thymus. However, some of the patients treated may have had partial DGS, which can improve on its own, so results in certain cases may have been coincidental.

Thymus transplantation

Allogeneic processed thymus tissue (Rethymic) is implanted surgically in the quadriceps muscle of the recipient. Approval of allogeneic processed thymus tissue was based on 10 prospective single-arm, open-label studies that included 105 patients from 1993 to 2020. Survival rates were analyzed with the longest follow-up period of 25.5 years. In the EAS, Kaplan-Meier estimated survival rates (95% CI) were 77% (0.670–0.841) at 1 year and 76% (0.658–0.832) at 2 years. For patients who were alive at 1 year post implantation, the estimated long-term survival rate was 94% at a median follow-up time of 10.7 years. For the patients in the clinical trials, naïve T-cell levels were measured using flow cytometry at 6, 12, and 24 months after implantation. Patients in the clinical trials started out with very few naïve T cells, but naïve CD4 and CD8 T cells began to reconstitute over the first year, with a durable increase through the second year. Reductions in the number of infections over time during the first 2 years after treatment were statistically significant (p < 0.001).[66]  

Early thymus transplantation (ie, before the onset of infectious complications) may promote successful immune reconstitution. (Goldsobel et al reported disappointing results for thymus transplantation, but a significant number of patients in their study were lost to follow-up.[67] ) Because T-cell function may improve in patients with partial 22q11.2DS, thymus transplantation is indicated only for patients with complete 22q11.2 DS, phenotypically similar to SCID.[36, 68, 69, 70, 71]

In a study by Markert et al of 5 patients with complete 22q11.2DS who were treated with allogeneic, cultured, postnatal thymus tissue, 4 patients displayed immune reconstitution with T-cell proliferative responses to mitogens.[72]

In a follow-up study, Markert and colleagues reviewed 54 patients with complete 22q11.2DS who were enrolled in protocols for thymus transplantation and found that 1 year after transplantation, 25 of 25 subjects tested had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Additionally, transplantation was fairly well tolerated; the most common adverse events were hypothyroidism and enteritis.[68]

At the time of the study’s publication, at which point posttransplant follow-up had been as long as 13 years, 33 of the 44 subjects who received a transplant were alive (75%). All deaths were reported to have occurred within 12 months of thymic transplantation.

Bone marrow transplantation

Adoptive transfer of mature T cells (ATMTC) through bone marrow transplantation has emerged as a successful therapy for complete 22q11.2DS, providing a potential alternative to thymic transplantation. Compared with thymic transplant, ATMTC is thought to be an easier procedure to accomplish and is available at more centers; however, there are differences in the nature of the T-cell reconstitution that results. Predictably, more naïve T cells and recent thymic emigrants are present in patients treated with thymus transplant.[73]

There are no significant differences in mortality between the 2 procedures, but the number of patients is too limited to conclude that the techniques are equally effective. Adoptive transfer will likely be pursued as a reasonable treatment for patients with 22q11.2DS who require immune reconstitution when thymus transplant is not available.[69]

Physical growth

Monitor growth in patients with 22q11.2DS. Feeding difficulties and failure to thrive are common in these patients, especially in those with a significant cleft palate. Occasionally, placement of a nasogastric or gastrostomy tube is necessary for feeding during the first 6-12 months of life. The tube provides adequate nutrition to prevent serious growth failure. Later, monitor the patient for growth hormone deficiency, which may manifest as significant short stature or deceleration of rate of growth in height. 22q11.2 DS–specific growth charts are available for Caucasian children.[74] In 2017, increased prevalence obesity was noted in adults with this syndrome, and prevention of obesity would be the ideal.[75]

Psychomotor development

Also monitor the child’s development. If there is a developmental delay, refer the patient for physical therapy, occupational therapy, and speech therapy evaluations. The patient should also be referred to a psychologist in order to be screened for learning and behavioral problems, starting at age 4 years and then again at ages 6-11, 12-18, and over 18 years.

Cleft palate can be repaired with surgical modalities.[2] As patients with 22q11.2DS grow older, correction of hypernasal speech becomes important; this can be performed initially with speech therapy, but surgery may be required.[76, 77] Consult a reconstructive surgeon experienced in treating velopharyngeal incompetence (VPI). Avoid adenoidectomy, as it may worsen the VPI. For the severely affected patients with hyper-nasal speech, the surgical results are not as good as in those who are moderately affected.[78]

In order to establish a more competent airway in patients with 22q11.2DS, congenital anterior glottic webs can be managed with surgical reconstruction or tracheotomy.[3]

Coordinated, multidisciplinary follow-up care is necessary to ensure that patients with 22q11.2DS receive optimal medical care; the following consultations should be obtained initially and during follow up[59] :

• Geneticist: For initial evaluation and genetic counseling, which will also include the choice of testing the parents of a child with 22q11.2; ongoing periodic follow-up consultations are recommended to apprise the family of new developments, to reinforce the counseling and recurrence risk assessment, and to direct the family to resources in the community[52]

• Pediatric cardiologist: For evaluation and management of cardiac disease

• Pediatric cardiothoracic surgeon: For help in the evaluation and correction of cardiac and great vessel defects

• Craniofacial specialist: For treatment of patients with cleft palate and feeding difficulties

• Otolaryngologist: When recurrent otitis media occurs and may be needed to manage structural abnormalities in the airway

• Audiologist: For hearing assessment

• Immunologist: For evaluation of immune function and for other immunologic disorders

• Infectious disease specialist: May assist in the management of recurrent infections

• Ophthalmologist: For assessment of ocular malformations

• Pediatric endocrinologist: For evaluation and management of hypocalcemia or for signs of thyroid or growth hormone deficiency

• Psychologist and psychiatrist: Starting at preschool age; psychiatric disorders are common in all patients with developmental delay; however, the association is stronger in patients with chromosome 22q11.2 deletion. Adults may develop schizophrenia and antipsychotic medications may need to be prescribed. One has to be cautious in using antipsychotics that can cause seizures.

Other specialists, such as an orthopedist, a neurologist for signs of Parkinson disease or seizures, or a nephrologist, may be needed based on the patient's signs and symptoms.

Approximately 8% of the patients with 22q11.2DS or velocardiofacial syndrome (VCFS) studied by Driscoll et al showed familial transmission of the 22q11.2 deletion.[79]

Because persons with 22q11.2 deletion have a 50% risk of transmitting it to each child, they should be offered genetic counseling, as well as fluorescent in situ hybridization (FISH) testing (by chorionic villus sampling) for prenatal detection as early as weeks 10-12 of gestation.

Studies have shown that 22q11 deletions occur in 20-30% of newborns with isolated conotruncal cardiac malformations. Therefore, screen all patients with conotruncal anomalies for 22q11 deletions, identify other family members at risk, and assess the risk in future pregnancies.

Autoimmune complications are commonly seen in 22q11.2DS patients with lower T-cell numbers at initial presentation increasing the risk of autoimmune complications. Thus monitoring parameters for autoimmune hemolytic anemia, ITP, rheumatolid arthritis, autoimmune thyroiditis, etc. is required. 

Neuropsychiatric complications such as learning disabilities are also common and are expected to become more apparent with age. Late neuropsychiatric complications may include schizophrenia and other neuropsychiatric conditions and these complications are implicated with deletion of the DGCR8 gene that controls miRNA production.

Medications are necessary when hypocalcemia or immunodeficiency is present. Treat patients with severely impaired T-cell function or profound lymphopenia prophylactically with trimethoprim/sulfamethoxazole, as directed by the immunologist. In patients with primary immune deficiencies, an immunologist should decide whether to initiate replacement therapy with intravenous (IV) immunoglobulin.

Calcium supplementation is necessary in patients with hypocalcemia. In rare cases in which calcium supplementation may not suffice, vitamin D may also be administered.

Class Summary

Surgically implanted allogeneic processed thymic tissue is intended to reconstitute immunity in children who are athymic. 

Allogeneic processed thymus tissue (Rethymic)

Indicated for immune reconstitution in pediatric patients with congenital athymia. 

Class Summary

These agents are used prophylactically in patients with immunodeficiency.

Sulfamethoxazole and trimethoprim (Bactrim, Septra)

This combination is used for prophylaxis. It inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. Sulfamethoxazole/trimethoprim should be prescribed based on recommendations from an immunologist.

Class Summary

Hypocalcemia may occur, requiring supplementation with calcium. In patients with symptoms refractory to calcium, supplementation with a vitamin D analog may also be necessary.

Calcium carbonate (Oystercal, Caltrate)

Calcium carbonate is used for the treatment and prevention of calcium depletion. Calcium moderates nerve and muscle performance by regulating the action potential excitation threshold. One gram of calcium carbonate equals 400 mg of elemental calcium. Calcium carbonate has higher oral bioavailability than other orally administered calcium salt products.

Calcitriol (Rocaltrol)

This agent is a vitamin D analogue and the primary active metabolite of vitamin D-3. Calcitriol increases calcium levels by promoting the absorption of calcium in the intestines and the retention of calcium in the kidneys. Its use should be initiated only upon an endocrinologist's recommendation.

Calcium gluconate (Kalcinate)

Calcium gluconate moderates nerve and muscle performance and facilitates normal cardiac function. It can initially be administered intravenously; a high-calcium diet can be used to maintain calcium levels. Some patients require oral calcium supplementation. The 10% IV solution provides 100 mg/mL of calcium gluconate, which equals 9 mg/mL (0.46 mEq/mL) of elemental calcium.

Ergocalciferol, vitamin D-2 (Drisdol)

This vitamin D-2 analogue is converted in the liver to an active intermediate and then further converted to its most active form in kidneys. Ergocalciferol effectively increases renal reabsorption of calcium, intestinal absorption of calcium, and calcium mobilization from bone to plasma.