Chromosome 22q11.2 Deletion Syndrome (DiGeorge... : Medicine (original) (raw)
INTRODUCTION
History and Nomenclature
The combination of cardiac anomalies and either hypocalcemia or recurrent infections has actually been reported in the medical literature for many years. Well before the role of the thymus was appreciated, one description in 1829 stands out for attempting to link a child with a syndrome that resembles chromosome 22q11.2 deletion syndrome with an absent thymus.57 The combination of thymic aplasia and congenital hypoparathyroidism was noted by Lobdell in 1959 and Sedlackova in 1955.89,131 In 1965, Dr. Angelo DiGeorge described a group of infants with congenital absence of the thymus and parathyroid glands.30 His name continues to be applied to the syndrome in cases where the etiology is not due to the hemizygous deletion. Subsequently, facial dysmorphia, conotruncal cardiac malformations, and speech delay were included in the spectrum and various other names came to be applied to this constellation of phenotypic features, including velocardiofacial syndrome, cardiofacial syndrome, and conotruncal anomaly face syndrome.22,72,137 The proliferation of names for a syndrome that is now known to have a unifying cause has been a source of confusion. In addition, patients with a clinical phenotype that is classic for the syndrome but is due to other causes add to the confusion. In an effort to be as systematic and precise as possible, it is now recommended that patients with the classic chromosome 22q11.2 deletion be described according to the genetic nomenclature, that is, the patient has chromosome 22q11.2 deletion syndrome, and patients with a clinical phenotype but a distinct cause or no known cause be described using syndromic nomenclature, that is, DiGeorge syndrome.
Pathophysiology
Cause of the Deletion
The deletion is bracketed by low copy number repeats (LCRs).38 Four discrete blocks of LCRs are found in this region and each block is comprised of multiple repeats.132 These blocks are named LCR A-D, with A being the most proximal (Figure 1). The deletion typically arises via unequal meiotic exchange, facilitated by asynchronous replication at the site of the deletion.11 The asynchronous replication can be associated with mispairing of the LCR and subsequent unequal crossing over.127 This mechanism predicts that duplications and deletions would be found in equal numbers. The characteristic deletion of chromosome 22q11.2 is at least 10 times more common than the next most frequent human deletion syndrome, suggesting that these repeat blocks are inherently unstable.133 The LCRs on chromosome 22q11.2 are larger and more complex and have higher homology than any of the other LCRs in the genome associated with human chromosomal deletion syndromes.
The genes within the commonly deleted region of chromosome 22. The smaller boxes represent the genes within the commonly deleted region. The larger boxes below the schematic chromosome represent the LCRs. The most common deletion, which is 3Mb, is seen in approximately 70%-80% of patients and occurs between the 2 most distant LCRs. Fifteen to 30% of patients have a slightly smaller 1.5 Mb deletion, and the remainder of patients have a variety of deletions with 1 breakpoint in an LCR.
Disease Mechanisms
The development of a TBX1 knockout mouse demonstrated the importance of this gene in cardiac development and defined impaired formation of the fourth branchial arch artery, a precursor to the right ventricle and outflow tract, as a critical component of the pathologic development.63,88,105 It remains controversial today whether other genes within the commonly deleted region contribute to the phenotype. Within the commonly deleted region of chromosome 22q11.2, there are over 35 genes. Mice generated to mimic the human deletion have a phenotype that is variable but replicates the most obvious phenotypic features in human patients.87 In mice, the phenotype of early embryonic fourth branchial arch defects is fully penetrant, but only a subset of mice have cardiac lesions at birth.
The discrepancy between the early branchial arch artery defect and the structure of the heart postnatally is extremely provocative and raises the question of whether an in utero intervention could be developed to counter the effects of the deletion. It could be envisioned that efforts to increase transcription of the functional chromosome could mitigate the effects if identified early enough.
The phenotypic variability in inbred mouse strains with the deletion or with the TBX1 knockout suggests that stochastic or subtle environmental factors contribute to the ultimate phenotype. Nevertheless, there is strong support for the concept that modifier genes contribute to the phenotype. When the deletion was bred onto other murine strains, the parathyroid and thymic phenotypes were enhanced. There is only modest evidence that this might occur in humans. Series of patients from the United States and Europe agree largely on the phenotypic manifestations;102,126 however, series from Chile, China, and South Africa have some significant differences that could represent ascertainment bias or true phenotypic differences related to distinct modifier genes.15,64,112,120 The availability of single nucleotide polymorphism (SNP) arrays has contributed to the identification of potential modifier genes and a VEGF polymorphism has been identified as a cardiac modifier.145
In mice, TBX1 is expressed in the pharyngeal mesenchyme and endodermal pouch. The pharyngeal pouches give rise to the face and upper thorax and are temporary structures. The third pouch gives rise to the parathyroid glands and thymus. Haplosufficiency for TBX1 leads to smaller precursor structures due to decreased proliferation of endoderm cells in the branchial arches and impaired pharyngeal artery development.166,170 The compromised arch development subsequently leads to aberrant development of the facial structures, parathyroid, and thymus. A cascade of transcription factors regulates the development of the parathyroid and thymus, and TBX1 is integrated into this cascade (Figure 2). TBX1 drives the expression of the downstream targets: FGF8, FGF10, MYF5, and MYOD.59,86,166,169-172 FGF8 and FGF10 support growth of surrounding cells and may also play a role in neural crest migration. MYF5 and MYOD regulate development of the branchiomeric muscles, perhaps explaining the swallowing dysfunction.71
The cascade of transcription factors regulating thymus and parathyroid development. The ovals indicate, from left to right, the transcription factor interactions required for thymic and parathyroid development. TBX1 regulates the expression of several growth factors and transcription factors, which are shown to the right of the bracket. Knockout mice for each of those genes have a phenotype which in part reproduces that seen in chromosome 22q11.2 deletion syndrome. The phenotypes of the knockout mice are indicated in parentheses next to each gene. The box at the bottom indicates a possible redundant pathway, whereby EYA1 and HOXA3 induce expression of GCM2, which is required for thymus and parathyroid development.
An important role of TBX1 is in the development of the secondary heart field. This structure is derived from the pharyngeal mesoderm and gives rise to the cardiac outflow tract, the right ventricle, and the mesenchyme of the brain. The primary heart field gives rise to the primitive linear tube and is not dependent on TBX1. TBX1 is expressed by a small number of cells in the anterior heart field which become cardiomyocytes in the outflow tract (Figure 3).93,166,170 The transcription factor cascade appears similar to that seen in the neck structures with Isl1 regulating SHH which induces the expression of a number of Fox family members. For the neck structures, this was FOXA2; in the secondary heart field it is FOXA2, FOXC1, and FOXC2. The Fox family members induce TBX1 expression, which then drives the expression of FGF8 and FGF10, which are important for survival, proliferation, and the migration of neural crest cells.58
TBX1 contributes to the right ventricle and outflow tract as well as the right atrium. The gray lines indicate the regions of the heart most consistently populated by cells derived from the anterior heart field that express TBX1. The aorta itself is infrequently populated, but the ductus arteriosus is almost completely derived from anterior heart field cells. Abbreviations: LA = left atrium, LV = left ventricle, PA = pulmonary artery, RA = right atrium, RV = right ventricle, SVC = superior vena cava.
There are recognized malformations that are not directly due to defects in the pharyngeal arches. Behavioral, cognitive, and psychiatric disturbances are extremely common, while distal skeletal anomalies, vertebral anomalies, and renal anomalies are seen in less than half the patients. The skeletal defects may be due to deficient TBX1 expression in the sclerotome. TBX1 is also expressed in the developing brain mesoderm, which may account for the neuropsychiatric findings.94
Recent advances in understanding the regulation of TBX1 have led to the possibility of regulating its expression through the retinoic acid pathway. Fetal isotretinoin exposure causes a syndrome similar to chromosome 22q11.2 deletion syndrome.24 Retinoic acid represses TBX1 expression,122 and therefore, manipulation of this pathway could represent a novel prenatal therapeutic strategy.
Other genes within the deleted region contribute to the phenotype of patients. Haplosufficiency for GPIbβ may contribute to the mild thrombocytopenia seen in patients, and haplosufficiency for COMT has been implicated in some studies as contributing to behavioral and psychiatric problems and may be related to the mild increase in malignancy.12,52,83,113 The CRKL gene has been deleted in certain patients with atypical deletions and has been implicated in the cardiac anomalies.56
Demographics
The estimated prevalence has been cited in several studies as being 1:3000-1:6000 births.49,153,163 These estimates are based on extrapolations of limited populations that have been screened using fluorescent in situ hybridization (FISH) technology. Males and females are equally affected, and there is no population "founder" effect. The deletion arises de novo frequently in all populations, and there is no reason to believe that the syndrome is more frequent in any particular ethnic background. The existing data do not yet take into account the rising prevalence due to increasing numbers of affected adults having their own affected children. Since this is a haplosufficiency disorder, one-half of the children of affected adults will have the deletion. Therefore, the prevalence is anticipated to rise over time. Currently, the figures are 6%-10% of new cases are familial.103 Since survival with cardiac anomalies was low until the mid-1980s, the familial cases are expected to rise. Moreover, within the Children's Hospital of Philadelphia (CHOP) cohort, the familial rate for patients with an atypical deletion such as the "B-D" deletion is much higher (5/11 or 45%), suggesting that those patients with a seemingly milder phenotype are more likely to reproduce.
Recent studies using SNP arrays have suggested that there are atypical deletions not detected by FISH-based strategies, and the true prevalence may be higher than suspected when these variants are included (see below). Commercial laboratories have reported classical deletions in approximately 1:100-1:200 samples sent for SNP array testing, and atypical deletions with approximately half of that frequency (Lisa Shaffer, Signature Genomics, personal communication). These laboratory sets represent patient cohorts with underlying medical problems but give valuable information on the relative frequencies of the typical and atypical deletions. Many of the atypical deletions would not have been identified with FISH technology, leading to the belief that we currently underascertain patients with the deletion.
While the frequency in the general population is slightly less frequent than trisomy 21, it is still sufficiently common that chromosome 22q11.2 deletion can occur in combination with other diagnoses. We have seen patients with Marfan syndrome and chromosome 22q11.2 deletion syndrome, Ehlers-Danlos and chromosome 22q11.2 deletion syndrome, and trisomy 21 and chromosome 22q11.2 deletion syndrome. There have also been distant family members with the deletion where it arose on completely distinct haplotypes and therefore represent distinct de novo events.
An important clinical aspect in the consideration of the demographic characteristics of the deletion is the frequency in unselected populations with compatible phenotypic features. The variability of the phenotypic features has made it difficult to define the exact clinical scenario where testing is warranted. Various algorithms have been developed to identify patient groups for whom testing for the deletion is clearly clinically warranted. These algorithms have thus far been disappointing at identifying patients outside of the most classic phenotype. Nevertheless, multiple studies have identified the frequency of the deletion in specific patient groups, and these data provide valuable context when considering the diagnostic approach (Table 1).
Frequency of the Chromosome 22q11.2 Deletion in Various Patient Populations*
Diagnosis
Chromosome 22q11.2 deletion was originally identified on the basis of a macroscopic deletion visible on a karyotype,70 but the typical deletion is submicroscopic and FISH has been used routinely to identify the heterozygous deletion since 1992. The FISH study is usually performed with a chromosome 22-specific probe that identifies the chromosome and a second probe that hybridizes to the commonly deleted region. If this second probe is absent on a "tagged" chromosome, then the diagnosis is established. The FISH analysis is very labor intensive and the technology requires substantial training and equipment. There are several commercial laboratories that perform FISH testing for a variety of chromosome defects, at a cost of approximately $750. There are 2 main issues with the FISH analysis specifically for chromosome 22q11.2 deletion. Due to the complexity of the assay, the turnaround time is often 3-14 days. For new parents, this can represent a substantial period of uncertainty. The second issue is that not all deletions have the typical A-D endpoints (see Figure 1). Atypical deletions that retain the region hybridizing to the probe cannot be detected by this technology.
Two alternatives to the FISH approach have been widely used. A PCR-based technology has been widely used in Europe; the results are rapid, and, due to multiplexing, it is very cost effective.144 In the United States, the approach which is gaining favor is the use of SNP arrays. These studies are usually twice as expensive, and the turnaround time is comparable to that of the FISH analysis. The advantage is that atypical deletions are identified with the same confidence as typical deletions, and other chromosome defects can be identified on the same assay. Use of the SNP array has led to the surprising finding that 15%-30% of the deletions are atypical. As the clinical findings are not necessarily different in patients with atypical deletions, this subset is just as important to identify as the patients with the typical deletion. The phenotypes of the patients with the atypical deletions and the patients with the duplications will be discussed below.
Many patients are now identified on prenatal ultrasound as having a compatible clinical feature that warrants testing for the deletion. When patients ultimately identified as having the deletion were examined, the majority had cardiac anomalies seen on prenatal ultrasound (Table 2). The identification of a cardiac anomaly on prenatal ultrasound should trigger testing for multiple potential causes, including chromosome 22q11.2 deletion. An interesting observation from this study is that polyhydramnios was seen in 16% of the prenatal ultrasounds of babies ultimately identified as having the deletion. While polyhydramnios is common, this finding in combination with another low-risk anomaly such as polydactyly, might also suggest the need for additional genetic testing.
Prenatal Ultrasound Findings in Patients With Chromosome 22q11.2 Deletion*
In addition to the case of a potentially affected fetus identified on prenatal ultrasound, there are cases where the index of suspicion is high for an affected fetus. A fetus at risk due to an affected parent deserves a higher level of screening than a fetus identified on prenatal ultrasound as having polydactyly. A fetus at risk due to a previously affected child, where the parents have been found to be genotypically normal, also deserves screening but the intensity may be less than for the fetus at risk due to an affected parent. The options for screening include a level II ultrasound at 16 weeks gestation, fetal echocardiography as early as 18 weeks gestation, chorionic villus sampling as early as 12 weeks gestation, and amniocentesis as early as 16 weeks gestation. Either FISH or SNP arrays may be performed on samples from amniocentesis and chorionic villi.
Families at risk due to a previously affected child most often desire parental testing to define the recurrence risk in future pregnancies. Parents who are found to carry the deletion require counseling to inform them of recurrence risks and the phenotypic heterogeneity. Parents who are both found to have a normal genotype could still potentially bear another affected child due to germline mosaicism. While uncommon, it should be considered in reproductive decisions. The recurrence risk to 2 parents with a previously affected child who are genotypically normal is generally cited as <1%.104
For parents who are known to have the deletion and who desire to maximize their chance of having unaffected children, there are 4 potential options. Some parents opt to conceive naturally and screen by 1 of the testing methods discussed above. Chorionic villus sampling allows the earliest detection of an affected fetus and termination if the parents wish. Preimplantation genetic diagnosis is still expensive, imperfect, and logistically difficult, but is becoming more widely available. Donor egg or donor sperm represents a more mainstream approach for some families. Finally, adoption of a child is a solution for some families. These discussions are difficult under any circumstances, and planning in advance can greatly smooth the process.
Atypical Deletions and Duplications
The mechanism of the deletion predicts that duplications occur as often as deletions. The fact that duplications are identified less frequently probably is due to ascertainment bias rather than fetal loss since the patients with duplications do not seem to have a particularly severe phenotype. Detection of a duplication is infrequent by FISH because the probes overlap visually, therefore our understanding of the frequency and the phenotype of patients with duplications is very limited. Using SNP arrays, the duplications have been found roughly half as frequently as the deletions, but the milder phenotype may have led to fewer studies being obtained. The phenotype of patients with duplications is most notable for developmental delay. Heart disease, including hypoplastic left heart syndrome; palatal anomalies; and hypocalcemia have all been seen with some frequency. Additional findings have included seizures, microcephaly, macrocephaly, tracheal stenosis, and hearing loss. It is striking that the features significantly overlap those of patients with the deletion.162 This has also been seen in murine models and a gain-of-function TBX1 mutation.85,173 The mechanism is not completely understood, but overexpression of TBX has been observed to down-regulate the retinoic acid metabolic pathway.21
The LCRs can mediate different breakpoints, and it has been hypothesized for many years that the breakpoints would predict the phenotype. Breakpoint-specific phenotypes have not been defined, in part because there were few opportunities to study the atypical deletions. It is anticipated that future studies will allow stratification to some extent based on breakpoints, and, in particular, the inclusion or exclusion of TBX1 in the deleted region. At this point, the findings are not sufficiently consistent to allow reliable patient stratification. Findings in patients with atypical deletions have included cardiac anomalies, palatal anomalies, renal defects, endocrine dysfunction, and developmental delay.
METHODS
For the literature search that forms the basis of the current study, we searched PubMed (National Library of Medicine, Bethesda, MD) for the years 1950 to 2010, using the search terms DiGeorge syndrome, velocardiofacial syndrome, TBX1, and chromosome 22q11.2.
The current study also includes new data from a cohort of children and adults followed longitudinally at CHOP. Patient inclusion in this cohort requires a confirmed hemizygous deletion of chromosome 22q11.2. Deletion detection has included FISH, SNP array analysis, and PCR analysis. Atypical deletions and duplications are not included in the standard cohort but are analyzed separately. Patient inclusion and study also requires a signed consent for data collection; data are updated semiannually and maintained in a secure database. This ongoing study has been approved by the Institutional Review Board; the photographs included for educational purposes were separately consented.
RESULTS
Phenotype
The phenotype is extraordinarily variable, even within families. It is useful to consider the phenotypic features according to their frequency in the population and their contribution to the patient's quality of life. The phenotypic features that most often mold the quality of life-the "major phenotypic features" discussed below-are developmental delay, cardiac anomalies, palatal anomalies, and the immune deficiency (Table 3). These features are common in the population bearing a deletion, and they often contribute substantially to the medical needs of the patient, particularly in early childhood. Although they did not analyze the entire database, previous studies of subsets of patients revealed that phenotypic features aggregated randomly.44,142 Specifically, the immune deficiency was equally likely to occur in patients with features of DiGeorge syndrome or minimal phenotypic features.147
Major Phenotypic Features*
The second category described below-the "intermediate phenotypic features"-comprises those phenotypic features that are less common in the population but still pose significant medical concerns when they are observed. These include renal anomalies, hypocalcemia, and feeding problems (Table 4). Other phenotypic features-"minor concerns"-contribute to the overall composite picture of the patient and can, in some cases, provide a valuable diagnostic clue but are not major contributors to the medical needs of the patient (Table 5). Finally, there are several rare but serious phenotypic features that should be considered in patients with compatible clinical features (Table 6). Each of these categories will be considered in turn.
Intermediate Phenotypic Features*
Minor Concerns*
Infrequent but Medically Significant Issues*
Major Phenotypic Features
Cardiac Anomalies
The types of cardiac defects seen in chromosome 22q11.2 deletion syndrome include tetralogy of Fallot, pulmonary atresia, truncus arteriosus, interrupted aortic arch, and ventricular septal defect.34,48,97 These findings in chromosome 22q11.2 deletion syndrome can be associated with additional cardiovascular anomalies that complicate the anatomy and surgical repair. The associated cardiovascular defects can be found at the level of the aortic arch, the pulmonary vascular tree, and within the heart itself. Particular features of the aortic arch include a right-sided aortic arch, a duplicated aortic arch/vascular ring, or a left-sided aortic arch with an aberrant right subclavian.19 Additional features seen in the pulmonary arterial tree include crossed arteries, hypoplasia of 1 artery, or hypoplastic pulmonary arteries.19 Within the heart, the septum can be hypoplastic or absent, and it can be displaced either anteriorly or posteriorly. There are also some valvular anomalies that are seen frequently in patients with chromosome 22q11.2 deletion syndrome, including dysplastic pulmonary, tricuspid, or aortic valves.19
Tetralogy of Fallot is one of the more common cardiac anomalies seen in this syndrome, and approximately half of the cases have additional features that complicate management and surgical repair.96,109 Of particular importance is the identification of a right-sided aortic arch, because this affects the surgical strategy for a systemic-pulmonary shunt. In general, tetralogy of Fallot is now repaired primarily without the need for an intervening palliative procedure. Another common finding in chromosome 22q11.2 deletion syndrome is pulmonary atresia with a ventricular septal defect. This is sometimes also known as tetralogy of Fallot with pulmonary atresia. In this cardiac anomaly, the pulmonary arterial perfusion is maintained by major aortopulmonary collateral arteries.62 This particular cardiac anomaly is categorized into 3 types with markedly differing prognoses. In some cases a primary repair can be performed and there are no additional risks to the patient compared to other children with the same cardiac anomaly.6 In cases where the pulmonary arteries are hypoplastic or nonexistent, typically the surgical repair includes a palliative procedure followed by a definitive surgical repair at a later time.29
Two other specific cardiac anomalies should be mentioned. Truncus arteriosus is a cardiac defect consisting of the single output from a heart supplying both the systemic and pulmonary circulation. The surgical timing and the technique used for this anomaly is highly patient-dependent. Generally, truncus arteriosus is repaired in the first few days of life because delay can lead to accelerated pulmonary vascular disease.154 Interrupted aortic arch is another common defect in patients. It is often categorized according to where the interruption occurs, with type C patients having an interruption between the innominate and left carotid artery, and type B patients having the interruption between the left carotid and left subclavian artery. There is also a type A interrupted aortic arch; however, this is not seen in patients with chromosome 22q11.2 deletion syndrome. As is true for patients with tetralogy of Fallot, these patients can have additional cardiac findings that can alter management.92 Specifically, the aortic valve can be bicuspid or associated with a hypoplastic aortic annulus. The infundibular septum can be hypoplastic, and there can be obstruction below the level of the aorta.
Immune System
The immune system is affected approximately 75% of the time, and the effects are thought to arise secondary to thymic hypoplasia. The size of the thymus does not predict circulating T-cell counts partly due to microscopic rests of thymic epithelial cells at aberrant locations.5 With a limited organ space for the development of T cells, the peripheral blood has a diminished supply of T cells, and T-cell counts are low. The severity ranges from absent thymic tissue and no circulating T cells to completely normal T-cell counts. Many infants with low T-cell counts will demonstrate improvement in the first year of life but after that, T-cell counts decline, as is seen in unaffected children. The age-dependent decline in T-cell numbers is slower in patients compared to controls, such that many adult patients have T-cell counts comparable to unaffected peers. Homeostatic proliferation appears to be responsible for the initial rise in infancy and the slower rate of decline of T-cell counts. Homeostatic proliferation represents an expansion of existing T cells rather than the generation of new T cells within the thymus. Homeostatic proliferation is typically associated with an advanced maturation of the T-cell compartment, and this is seen.82,117 Spontaneous apoptosis is increased in patients compared to controls, consistent with an acquired functional defect due to the homeostatic proliferation.55 Early changes in the T-cell repertoire are seen because as the limited T cells expand in number, there are no new T-cell specificities developed. New T-cell specificities can only arise from thymically derived T cells. The changes in naive and memory T cells progress further with aging, as do the defects in repertoire (deletions, oligoclonality).18,118
The import of these findings is that a prematurely senescent T-cell compartment would be anticipated to be less effective in antiviral defenses and less effective in delivering help to B cells for antibody production; however, there are no clinical data to suggest that adults have increasing infections with age.67,82
Most pediatric patients have a mild to moderate decrease in the mean number of CD3+ T cells compared to age-matched controls.23,61,66,67,76,130,148 T-cell proliferation is normal in the majority of patients and when decreased is simply reflecting the low frequency of responder cells.10,23,66,76 The majority of patients with the deletion are modestly immunocompromised and do not develop opportunistic infections. Viral infections can be prolonged, and abnormal palatal anatomy may lead to compromised drainage and an increased susceptibility to upper airway bacterial infections. With the exception of very immunocompromised children, live viral vaccines may be safely given. No special precautions need to be taken to prevent graft-versus-host disease or opportunistic infections except in those patients with very severe immunocompromise. Having said that, the more typical patients are not immunologically normal. Adults and children over the age of 9 years have significant infections. Only 40% of patients aged >9 years with the deletion were thought to be as healthy as others their age. Approximately one-quarter to one-third of the patients had either recurrent sinusitis or otitis media, and 4%-7% had recurrent lower airway infections.61
There are secondary consequences to the limited thymic output. Antibody production and function are largely intact in patients with chromosome 22q11.2 deletion syndrome.66 Nevertheless, there are rare patients with significant antibody dysfunction that are indistinguishable from a patient with common variable immune deficiency. In many cases, the antibody production will improve over time, but not always. Less severe antibody dysfunction has also been described: immunoglobulin A (IgA) deficiency, impaired responses to vaccines, and transient hypogammaglobulinemia of infancy have all been described.41,43,141 A more severe infection pattern may correlate with immunoglobulin abnormalities.41,43
One secondary consequence of the immune deficiency is autoimmune disease, seen in approximately 10% of patients.61 Juvenile idiopathic arthritis and hematologic autoimmune diseases are the most common disorders, but there is a generalized susceptibility to autoimmunity rather than an association with a specific disease.25,26,61,77 Idiopathic thrombocytopenia pupura is the most common condition, occurring in 4% of patients, although platelet size and number are slightly aberrant in most patients with the deletion due to haplosufficiency for the platelet protein GPIbβ.83 Celiac disease may be more common than in the general population, and there are reports of other autoimmune processes occurring sporadically.31 The mechanism underlying the susceptibility to autoimmune disease is not well established but homeostatic expansion selects for self-reactive T cells. A decrease in regulatory T cells has also been seen,149 which could contribute to the predisposition to autoimmunity.
An increase in allergic diseases is seen in chromosome 22q11.2 deletion syndrome,146 contributing to the infection pattern, and this predisposition to allergy may also be related to the homeostatic expansion because Th2 differentiation appears to be the default pathway in homeostatic proliferation in mice.107
Some infants with thymic aplasia due to DiGeorge syndrome or chromosome 22q11.2 deletion syndrome have a dramatic oligoclonal expansion with infiltration into end organs.98 The T-cell counts are often quite high but do not reflect the adequacy of the T-cell compartment since they are expanded from a very small number of founder T cells. Often the infants have erythroderma, similar to what is seen in Omenn syndrome. The T cells are predominantly or almost exclusively of a memory phenotype (CD4/CD45RO or T-cell receptor excision circle [TREC] negative), and the repertoire is oligoclonal.98,119 These patients require significant immune suppression before transplantation.
Palatal Defects and Speech Mechanism
The palate is affected in the majority of patients and contributes to poor feeding, speech quality, and speech acquisition. The most common type of defect represents a muscular weakness and affects the ability to close off the nasopharynx when swallowing and speaking. It is not obvious on standard physical examination, and special testing must be used to characterize the degree of weakness. This velopharyngeal weakness contributes to the nasal regurgitation seen in babies when they drink liquids and is the major contributor to the hypernasal speech. More significant palatal defects can include submucous clefts and frank anatomical clefts, but cleft lip is relatively uncommon.102 Although the palatal defects are not generally life-threatening, they can be distressing to the parents and interfere with feeding and secondarily the bonding that accompanies feeding. The palatal phenotype is modified by sex and race variables in a way that is not understood.37
Studies of the anatomy supporting the pharynx have shown that the cranial base is shorter and the palatal angle is higher. A greater depth of the pharyngeal cavity has also been seen and this no doubt contributes to the hypernasal speech.159 The mechanics of speech can be affected in this syndrome. Phonation can be aberrant due to laryngeal webs, velopharyngeal insufficiency, or vocal cord paralysis. The latter can be iatrogenic due to damage at the time of cardiac surgery. Hoarseness and hypernasality respond to surgical intervention, but phonation remains somewhat abnormal in many cases.90,91 Ultimately most patients learn to speak and communicate effectively.
Development
The degree of developmental delay is highly variable. Motor delay is often one of the first features identified by parents. The mean full-scale IQ is approximately 70, with a range from normal to moderately disabled.44,150,151 However, 65% of individuals are found to have a nonverbal learning disability with a >10 point split between their verbal and performance IQ, with verbal IQ being higher and thus translating into relative strengths in the areas of verbal memory, reading, and rote memorization, with deficits in the areas of mathematics, visuospatial memory, and abstract reasoning. Therefore, in general, full-scale IQs do not accurately represent most patients, and their verbal and performance IQs should often be considered separately. This has direct ramifications for educational interventions.164 Furthermore, comprehension and social rules also represent strengths in many. In young children, motor skills are affected moderately (with a mean age of walking at 18 mo), and visuo-perceptual abilities and planning tend to be weak with concomitant language deficits and social-emotional concern.44,142,143,164
The cause of the developmental delay has been extensively investigated. Nearly 10% of patients have microcephaly with the parietal lobe most often involved.7,16 A small vermis is detected in patients with chromosome 22q11.2 deletion syndrome similar to that seen in individuals with autistic spectrum disorder.12 The posterior vermis is implicated in social drive, and this may explain some of the social awkwardness seen in certain patients with chromosome 22q11.2 deletion syndrome. To examine cognition, several modalities have been used. Functional magnetic resonance imaging (MRI) studies have shown that the patterns of brain use during mathematical tasks are different in patients with chromosome 22q11.2 deletion syndrome compared to controls,7,139,140 suggesting that neural connections are aberrant.
Speech development is one of the most troubling aspects of chromosome 22q11.2 deletion syndrome for many parents. Expressive language and speech skills are typically delayed while receptive skills are near normal. The mean age of speaking is 30 months. Management of speech delay in this syndrome is controversial. Proponents of sign language feel that the ability to communicate is of paramount importance. Signing allows the child to communicate and diminishes frustrations as well as the behavioral consequences of frustration.142,143 Proponents of natural speech feel signing delays acquisition of speech.47
Intermediate Phenotypic Features
The phenotypic features of the intermediate class comprise those features that are less common but still medically important. In any particular child, the effects of the feature may loom large, but these features do not dominate the medical care in the cohort overall (see Table 4).
Gastrointestinal Issues
Gastrointestinal issues are common in the population and represent a particular source of frustration for families. A myriad of problems such as intestinal malrotation, nonrotation, Hirshprung disease, imperforate anus, esophageal atresia, tracheoesophageal fistula, and congenital diaphragmatic hernia can affect a child and can secondarily affect the feeding behaviors.32,102 A fairly global motility effect is seen in patients, although one manifestation may be more obvious in any given child.39 Constipation is a final common denominator of the dysmotility and reflux may also be traced to the global dysmotility defect.
Hypocalcemia
Hypocalcemia is common during and after cardiac surgery in any child and is often noted in children with chromosome 22q11.2 deletion.102,126 Sustained hypocalcemia is much less common. Oral calcium supplementation with or without vitamin D is typically sufficient. Oversupplementation leads to nephrocalcinosis and a balance is required. Most children do not require prolonged calcium supplementation, although some cases require lifelong supplementation. In addition, late onset or recurrence of hypocalcemia have been described, often revealed during times of metabolic stress such as illness, puberty, or pregnancy.
Renal Defects
Kidneys are affected in roughly one-third of patients but a smaller number have ongoing medical needs related to their renal abnormalities. Dysplastic kidneys requiring dialysis is fortunately seen infrequently, but can have a devastating effect on the overall health of the child. Renal agenesis is also uncommon but can have a similarly devastating effect on the quality of life.28,165
Hearing
Most patients have posteriorly rotated ears or simple helices as external ear phenotypes, but a minority have permanent hearing loss. Hearing loss contributes to the delayed speech seen in this syndrome, and hearing loss should be identified and addressed as rapidly as possible. Detailed vestibular testing of patients has not been performed, but both conductive (45%) and sensorineural hearing loss (2%-15%) have been described.36 The conductive hearing loss is often associated with palatal anomalies, but microtia and anotia have been described infrequently.35
The murine models of chromosome 22q11.2 deletion syndrome show a more dramatic otic phenotype than is seen in humans. In the TBX1 knockout mouse, cochlear development is markedly abnormal, and the interaction of TBX1 and a transcription factor called Brn4 has been shown to be necessary for periotic mesenchyme development.14,157
Feeding and Swallowing
Feeding issues can be extremely difficult for parents in early infancy. Feeding and swallowing problems appear to arise from poor coordination of the pharyngeal muscles, tongue, and esophageal muscles.123 Patients with cardiac defects might also have shortness of breath, leading to poor feeding, and breast feeding is known to be difficult for patients with palatal clefting. Thus, many variables may contribute to poor feeding.
Dental Issues
There are few data on the dental issues facing children and adults. Delayed eruption of the primary teeth and enamel hypoplasia have been described.74 Hypodontia has been described in case reports,168 but the frequency of this finding is not known.
Structural CNS Anomalies
As a very gross measure, head circumference was measured in 73 patients.33 The head circumference was below the 3rd percentile in 9.6%, between the 3rd and 25th percentiles in 49.3%, between the 25th and 75th percentiles in 27.3%, and between the 75th and 97th percentiles in 13.7%. Therefore, microcephaly is common, but is not a consistent feature. The import of the microcephaly is its association with other CNS anomalies and with functional deficits.
MRI analyses have shown that gray matter is reduced, particularly in the frontal cortices, the cingulate gyrus, and the cerebellum. These gray matter findings correlated with poor attention and executive functioning.135 Additional MRI findings of gray matter reductions have been correlated with the propensity to develop schizophrenia.129,152 Polymicrogyria can be associated with microcephaly, and this occurrence is devastating for families as it severely compromises development.
To better characterize the learning disabilities in this syndrome, functional MRI approaches have been taken. This approach is based on the concept that aberrant function can be identified by visually inspecting neural circuitry as patients perform specific tasks. Because of the clinical observation that patients struggle with visuo-spatial processing,139 many of the studies have focused on these types of tasks. The parietal and occipital lobes are generally involved in this type of processing, and patients activate these pathways less well than controls.17,69 It has been proposed that this type of defect cascades into other types of learning,138 and indeed, this type of processing problem is nearly unique to this syndrome and is associated with a specific learning disability.155
Spinal Abnormalities
Cervical spine instability has been described in various patients. Midline C1 defects, C2-C3 fusions, and morphologic changes in the C2 vertebra are seen commonly but are of uncertain clinical significance.75,121 Also commonly seen are butterfly vertebrae and hemivertebrae. The hemivertebrae can be clinically significant when associated with scoliosis. In our cohort, the frequency of butterfly vertebrae is 11%.108
Ophthalmic Anomalies
Ophthalmologic anomalies were not initially appreciated in this syndrome. Minor dysmorphia such as hooding of the eyes and narrow palpebral fissures had been noted but functionally important defects have been characterized only in the last few years. Refractive errors are more common than in the general population with astigmatism and hypermetropia being the most common.20,95 Ophthalmologic examinations will often show posterior embryotoxon, which is a developmental defect of the Schwalbe line. Tortuous retinal vessels are also quite common, seen in approximately 75% of patients.20 More significant functional impairments due to sclerocornea, Peter anomaly, and coloboma have been described less frequently.20 The high frequency of refractive errors and the infrequent but severe functional defects mandate that children have an ophthalmologic assessment.
Behavioral and Neuropsychiatric Aspects
The behavioral aspects of chromosome 22q11.2 deletion syndrome include attention deficit hyperactivity disorder, poor social interaction skills, and impulsivity.3,80,114,115 Frank psychiatric disorders are also seen with bipolar disorder, autistic spectrum disorder, and schizophrenia/schizoaffective disorder found in 10%-30% of older patients. There are no well-controlled studies on the prevalence of psychiatric disorders in young children with chromosome 22q11.2 deletion syndrome; however, it is suspected that the behavior patterns are set relatively early in life. Studies of school-aged children have shown a number of abnormal behaviors even in that young population. Several studies have demonstrated a high frequency of attention deficit hyperactivity disorder (3%-46%), oppositional defiant disorder (16%-43%), phobias (23%-61%), generalized anxiety disorder (17%-29%), and obsessive-compulsive disorders (4%-33%).3,4,40,53 Autistic spectrum disorders have also been seen with a high frequency (14%-45%), and the contribution of this phenotype to bipolar affective disorders and schizophrenia is not yet known.2,158
Behavioral problems and psychiatric disorders are in general, more common in people with developmental delay. The high frequency in patients with chromosome 22q11.2 deletion syndrome suggests a very specific effect from the deletion.60 This, in combination with the functional MRI findings as well as specific defects in gray matter development, suggests that the deletion leads to a specific predisposition to behavioral and psychiatric disorders.54
Many of the studies of psychiatric disorders have been performed in adults. Up to one-third of patients may have psychiatric disorders in adulthood.8,50,65,113 The majority of these psychiatric disorders are schizophrenia and schizoaffective disorder. There has been intense interest in early identification of patients predisposed to schizophrenia, and 1 study identified internalizing symptoms, anxiety, and depression as strong predictors in childhood of the subsequent development of psychotic disorders in adulthood.51 Obsessive-compulsive disorder was a particularly strong predictor of later psychiatric problems.51 Another strategy to predict the later development of psychiatric disorders is based on the functional polymorphism of the enzyme catechol-O-methyltransferase. This enzyme metabolizes dopamine and is expressed at high levels in the prefrontal cortex.84 The high-function variant, COMT-Valine, is associated with higher neuronal activation status. The low-function variant, COMT-Methionine, is associated with a variety of psychiatric diseases in the general population. The COMT gene is located within the commonly deleted region and has been presumed to contribute to the psychiatric phenotype in the syndrome. Studies of the variants contributing to the psychiatric phenotype have been conflicting, but it remains generally accepted that haplosufficiency for COMT contributes to the cognitive and behavioral findings.13,45,50,68,79
Minor Concerns
The minor concerns are notable for contributing to the overall impression of the patient that helps to develop the diagnostic approach. While posteriorly rotated ears might not trigger a diagnostic evaluation in isolation, in combination with tetralogy of Fallot, they would probably lead most people to assess the patient for the deletion. An important consideration is the different dysmorphic features seen in different racial groups and at different ages (Figure 4).15,64,112,120
Dysmorphic facial features differ in young and old and between races. Micrognathia becomes less obvious with age. Ear findings remain distinctive. Certain facial dysmorphic features are less prominent in other racial backgrounds. Note the asymmetric crying facies on the boy on the left. Other features of note are the hooded eyes and the broad nasal root on the boy on the left. (Photographs used with consent.)
Management
Time Frame of Needs
The management of patients with chromosome 22q11.2 deletion syndrome varies by age and phenotype (Figure 5). Most patients are identified shortly after birth due to the presence of a cardiac anomaly. In newborns, a physical examination, laboratory studies, and radiographic studies should target high-impact problems such as cardiac anomalies, hypocalcemia, severe immunodeficiency, or intestinal malrotation. Infancy is also a time when feeding issues can be distressing to parents.123 The toddler age mandates a focus on development and speech, while the school age years require attention to cognitive development. Behavioral and psychiatric disorders are seen in teenagers and adults. Anticipatory guidance for patients is difficult due to the heterogeneity in phenotype and the needs of patients, but a logical approach to the evolution of medical needs is essential.
The dynamic nature of health concerns in patients with chromosome 22q11.2 deletion syndrome. Each age has a typical set of concerns that change over time.
Mortality
The mortality rate in chromosome 22q11.2 deletion syndrome is not known. The rate of death in childhood is rare and is largely attributable to cardiac disease. In the cohort at CHOP, the mortality rate in childhood has been 4%. This is lower than the rate observed in other older cohorts and may reflect improved cardiac care.78 The rare patients with complete thymic aplasia and absent T cells have a high mortality rate, but this phenotype is seen in less than 1% of patients.99 The data have been much more difficult to collect in adults. There are theoretical reasons to consider the possibility of a shortened life expectancy, and 1 study appears to support a shortened life expectancy.9 Nevertheless, much work is required to define life expectancy fully.
Cardiac Management
Cardiac surgeons are often the first to consider chromosome 22q11.2 deletion syndrome. At the time of cardiac surgery, they may note the absence of a thymus gland, which can be a clear sign of the syndrome. An absent thymus gland does not always portend a severe immune deficiency but can be associated with absent T cells. When T cells are absent, it is important to prevent graft-versus-host disease from the transfused blood products. This can be done by irradiating the blood.
In terms of preoperative diagnosis of the specific cardiac anomaly, echocardiography is performed in all cases and cardiac catheterization is performed in most cases. MRI can improve the diagnosis of additional vascular defects and bronchial compression and define the positions before surgery.
The perioperative care of patients with chromosome 22q11.2 deletion syndrome is complicated by not only the immune deficiency but also hypocalcemia.128 In some centers, cardiac patients with the deletion are managed with a modified perioperative antimicrobial strategy, whereas in other centers they receive the same perioperative care as other patients.19 The immune deficiency in these patients is sometimes not carefully characterized before surgery, and therefore it seems warranted to err on the side of caution by using enhanced antimicrobial prophylaxis. These patients seem to exhibit vasomotor instability as well as bronchospasm, and the potential association of the laryngeal web and tracheomalacia can sometimes require modification of the perioperative care.1,134
Patient outcomes after cardiac repair are in some ways comparable to the general population and in some ways different from the general population. Feeding difficulties can delay discharge from the hospital, and developmental delay can cause concern. Initially it was difficult to distinguish between surgically induced neurodevelopmental outcome issues and issues related to the deletion. The fact that there are significant developmental delays in children with the deletion who have not had cardiac surgery suggests strongly that the majority of the neurodevelopmental outcome issues in patients with the deletion are related to the deletion and not the cardiac surgery.
Immune System-Mild to Moderate Immune Deficiency
Children with chromosome 22q11.2 deletion syndrome most often have a mild to moderate decrease in the peripheral blood T-cell count. T-cell proliferative responses are often normal.23,61 Compared to a population with human immunodeficiency virus (HIV) with similar T-cell counts, patients with the deletion do much better clinically. Opportunistic infections are infrequent,126 and the most commonly described issue is prolonged viral infections with or without secondary bacterial infections in early childhood. The frequency of these infections does not correlate with T-cell counts, suggesting that anatomy may be the major contributor to symptoms in upper respiratory tract infections.147
Clinical studies of patients do not demonstrate a susceptibility to opportunistic infections for the vast majority of patients, and the risk of live viral vaccine administration in infants is low with the exception of patients with thymic aplasia and absent T cells.111,116 It would not be appropriate to give live viral vaccines to patients with severe T-cell compromise.
Immune System-Thymic Aplasia
The patients with true thymic aplasia and absent T cells represent a very specific group. The genetic etiologies are different, with chromosome 22q11.2 deletion being found only in approximately half.99 It is not always clear at which point a thymus transplant or a fully matched T-cell transplant would be appropriate. An evaluation of the naive T-cell count or a measure of TREC in early infancy can be used to estimate the potential for thymic production of T cells, but the counts can change substantially over a few months. Two interventions have life-saving potential: a thymus transplant or a fully matched T-cell transplant. For a thymus transplant, thymic tissue is harvested and mature T cells capable of causing graft-versus-host disease are eliminated.100 Thin slices of the cultured thymus are implanted in the quadriceps muscle.101 Functional T cells appear at approximately 3-4 months posttransplantation.27 The implanted thymus involutes and does not sustain prolonged production of T cells; however, sufficient numbers are produced to provide adequate host defense and patients do well clinically.99 An alternative approach uses a fully matched donor, and peripheral blood T cells rather than stem cells are transplanted into the recipient.81
Hypocalcemia
Hypocalcemia is treated perioperatively with intravenous calcium supplementation. Home management depends on the level of hypoparathyroidism. Many patients will not require supplementation at home. For those who do, calcium is usually administered orally and vitamin D is given. Parathyroid hormone is an alternative. It is critical to monitor the supplementation because patients can "outgrow" their need for supplementation as the existing parathyroid cells hypertrophy. Oversupplementation can lead to nephrocalcinosis. Conversely, there are rare patients who in times of metabolic stress (pregnancy, acute illness, puberty, trauma) will reveal a latent hypoparathyroidism and require transient supplementation.
Palatal Defects
The palate is abnormal functionally in most patients. Not all require surgery; the decision must be individualized to the anatomy and the goals of the patient. Computer reconstruction and functional testing are often done to assess the best approach.125 The effectiveness of surgical repair in this syndrome appears to be roughly comparable to that seen in other patients.106,124 There are some concerns that the anatomic and functional abnormalities associated with the 22q11.2 deletion may impair velopharyngeal valving despite surgical management since all operative procedures for the management of velopharyngeal insufficiency rely on at least some intrinsic velopharyngeal muscle activity in order to achieve valve closure. Patients with a hypodynamic velopharynx frequently demonstrate persistent hypernasality despite surgical narrowing of the velopharyngeal orifice. A later surgical procedure than nonsyndromic cleft palate patients might affect overall results after speech surgery.73
Two issues related to the oral features should be mentioned. In general, the adenoid tissue provides a cushion that improves nasopharyngeal closure. Therefore, removal of the adenoidal tissue is not advisable in most cases. Tonsillectomies can be performed safely, but carotid arteries can be mal-positioned, and visualization before surgery is recommended to prevent accidental incision. The second issue is the high rate of otitis media, and it is common practice to place ventilation tubes in this patient population.
ILLUSTRATIVE CASES
Anecdotal evidence should never substitute for evidence-based approaches; however, examination of several illustrative cases will serve to amplify the importance of considering the entire panoply of phenotypic features as explanations for unusual symptom complexes. A case where a rare finding was identified after an intensive diagnostic evaluation is presented. Two additional cases illustrating management conundrums are also presented.
Case 1
A newborn male was found to have intestinal malrotation. A genetic evaluation identified minimal dysmorphic facial features but found abnormal ear helices and on the basis of 2 congenital anomalies, sent FISH testing for chromosome 22q11.2 deletion. The test came back positive and the family received genetic counseling. The child was seen by all appropriate specialties and was not found to have any other congenital anomalies or any significant health concerns. He did well and was followed by his pediatrician without any further health needs. As a 3-year-old, he developed abdominal pain, which was severe enough to require a visit to the emergency room. He was treated for constipation; however, his symptoms increased and his abdominal pain became intractable. An abdominal X-ray demonstrated a diaphragmatic hernia (Figure 6), and he received emergency surgery. At last follow-up, he was aged 9 years, doing well in school and with no further health concerns.
Case 1. The diaphragmatic hernia in the child completely filled his left chest.
Case 2
A 4-year-old girl diagnosed with the deletion shortly after birth had idiopathic thrombocytopenic purpura for 15 months. This was initially managed successfully with steroids but she was left untreated and had a mean platelet count of 25,000/mm3 for the past 3 months off all treatment. Two weeks ago she was hospitalized for autoimmune hemolytic anemia, which was treated with steroids with no clear improvement. Furthermore, with the most recent course of steroids, her platelet count remained at approximately 25,000/mm3.
The potential options discussed for management included splenectomy, rituximab, cyclosporine, and vincristine. The discussion centered around the appropriate strategy in a patient with a total T-cell count of 720 cells/mm3, a count approximately half the lower limit of normal for her age. Cyclosporine would target her "weakest" immunologic compartment, while rituximab would target her "stronger" immunologic compartment. Vincristine and splenectomy would also render the patient more significantly immune compromised.
The patient was treated successfully with rituximab, and she had complete resolution of both the autoimmune hemolytic anemia and the idiopathic thrombocytopenia purpura. Several months later, both cytopenias relapsed and she was again treated successfully with rituximab. She had several more cycles of rituximab and developed significant hypogammaglobulinemia, requiring immunoglobulin replacement therapy.
This case highlights our current lack of understanding about applying standard therapies for autoimmune disease to a patient population with preexisting immune compromise.
Case 3
An adult with chromosome 22q11.2 deletion syndrome was identified as having the deletion when her first child was found to be affected (Figure 7). Her first child suffered from a broad range of severe manifestations and required multiple hospital admissions. The mother had relatively modest manifestations of the deletion and was interested in having another child, but she sought reassurance that the next child would either be unaffected or have milder manifestations, similar to her phenotype.
Case 3. Dysmorphic facial features of child mentioned in case. The affected child had several features common to children with chromosome 22q11.2 deletion syndrome, including hooded eyes, a bulbous nasal tip, a small chin, and a crumpled ear helix. (Photographs used with consent.)
A genetic counselor met with the woman and discussed our current inability to predict phenotype in any given pregnancy. The woman was offered prenatal ultrasound as a screen for an affected fetus. The woman voiced understanding and the plan was reviewed to meet again when the pregnancy occurred.
Two years later, the woman became pregnant and on routine ultrasound was found to be carrying a child with tetralogy of Fallot. She met with the counselor and voiced concern about the severity of the heart defect in her fetus. She did not recall the content of the previous conversation and was distressed to learn that her options were to carry the fetus to term, knowing it could have significant health concerns, or to terminate the pregnancy. She ultimately carried the baby to term and placed the child for adoption.
This case highlights the very real-life consequences of learning disability in adults. This woman was not able to conceptualize the difficult decisions she ultimately faced. The ability to weigh abstract risks and benefits is a weakness in this population, and counseling must take these weaknesses into consideration for effective health care delivery.
DISCUSSION
The diagnosis of chromosome 22q11.2 deletion syndrome is relatively straightforward once considered. The testing is widely available and reliable. Nevertheless, there are several syndromes that can cause diagnostic confusion. Figure 8 demonstrates the overlap of phenotypic features with other syndromes. CHARGE (coloboma-heart-atresia-retarded-genital-ear) syndrome represents a particular source of confusion, as does Smith-Lemli-Opitz syndrome, Kabuki syndrome, and Goldenhar syndrome. Because these syndromes can have distinct inheritance patterns, it is critical to establish the correct diagnosis. Once chromosome 22q11.2 deletion syndrome enters the differential diagnosis, multiple testing strategies are available.
Syndromes causing potential diagnostic confusion. Elements of the phenotype can be seen with many other syndromes; however, a relatively small number consistently pose the potential for diagnostic confusion. This figure demonstrates some of the more common overlap features. Abbreviations: CHARGE = coloboma-heart-atresia-retarded-genital-ear syndrome.
More significant issues relate to management of patients once the diagnosis is established. The varied presentations and the varied phenotypic constellations mandate that each patient have a nearly unique management strategy. Nevertheless, coordinated care and comprehensive approaches are possible. The care of patients with chromosome 22q11.2 deletion syndrome clearly requires a multidisciplinary approach. It is important to prepare families for the changing tapestry of care needs, but also to respect the individuality of the patient. The phenotypic spectrum is broad and the changing needs over time make it impossible to predict with any certainty the ultimate level of function and the medical issues that will be most critical in any individual patient. A comprehensive care plan that addresses both the common and the uncommon features of the syndrome can be valuable for patients.
While clinical care has focused on optimizing currently available approaches for patients, research on the genetics and the cellular pathways has proceeded very quickly. In the future, the potential for intervention during fetal development holds promise, and the possibility of improved interventions for neuropsychiatric needs could lead to enhanced adult function.
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