22q11.2 deletion syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ayushi Jain, M.B.B.S[3]
Synonyms and keywords: DiGeorge syndrome; Velocardiofacial syndrome; Di George syndrome; Strong syndrome; third and fourth pharyngeal arch syndrome of Di George; CATCH phenotype; conotruncal anomaly face syndrome
Overview
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ayushi Jain, M.B.B.S[3]
Overview
22q11.2 deletion syndrome is a disorder caused by the deletion of a small part of chromosome 22. It occurs in approximately 1:4000 births.[1]
The deletion occurs near the middle of the chromosome at a location designated q11.2.
DiGeorge Syndrome (DGS) is a combination of signs and symptoms caused by defects in the development of structures derived from the pharyngeal arches during embryogenesis. Key findings comprises of thymic hypoplasia, hypocalcaemia, outflow tract defects of the heart, and dysmorphic facies.
The manifestations of this syndrome cross all medical specialties, and care of the children and adults can be complex. Many patients have a mild to moderate immune deficiency, and the majority of patients have a cardiac anomaly. Additional features include renal anomalies, eye anomalies, hypoparathyroidism, skeletal defects, and developmental delay. Each child’s needs must be tailored to his or her specific medical problems, and as the child transitions to adulthood, additional issues will arise. A holistic approach, addressing medical and behavioral needs, can be very helpful.
[2]
Historical Perspective
DGS characteristics were first described in 1828 but adequately reported later in 1965 by Dr. Angelo DiGeorge, as a clinical trial that included immunodeficiency, hypoparathyroidism, and congenital heart disease.
Historically, DGS was grouped within a sphere of other syndromes such as Shprintzen-Goldberg syndrome, velocardiofacial syndrome, Cayler cardiofacial syndrome, Sedlackova syndrome, conotruncal anomaly face syndrome, and DGS, collectively called 22q11 deletion syndromes. They have the same genetic etiology but their varying phenotypes has has led to confusion in diagnosing patients with DGS, which causes potentially catastrophic delays in diagnosis.
Classification
There is no established system for the classification of DGS.
Pathophysiology
The main factor leading to DGS is the deletion of 22q11.2, which encodes over 90 genes.
The 22q11.2 deletion syndrome can be inherited in an autosomal dominant manner. Prenatal testing, such as amniocentesis, is available for pregnancies determined to be at risk. Also pregnancies who have findings of congenital heart disease and/or cleft palate detected by ultrasound examination may be offered prenatal testing. Genetic counseling may be helpful for families who may have DiGeorge syndrome. Because most of the signs of this cluster of defects can also be inherited as autosomal recessive or x-linked traits, only genetic testing of both parents can determine with any certainty the likelihood these anomalies occurring in any subsequent children.
Causes
Most cases are linked to microdeletion of chromosome 22, at the long arm (q) at the 11.2 locus.
Differentiating [Disease] from Other Diseases
DGS must be differentiated from other diseases that cause similar clinical features and have a broad spectrum of presentation. All of the clinical findings associated with 22q11.2 deletion syndrome (22q11.2DS) can also occur as an isolated anomaly in an otherwise healthy individual. Genetic disorders and teratogenic exposures that may cause a clinical phenotype similar to 22q11.2DS are discussed in this section.
Epidemiology and Demographics
22q11.2 deletion syndrome affects an estimated 25 in 100,000 live births. Microdeletion of 22q11.2 is the most common microdeletion syndrome, affecting approximately 0.1% of fetuses. The rate of 22q11.2 microdeletion in live births occurs at an estimated rate of 1 in 4000 to 6000.
Risk Factors
The only known risk factor is that of a family history of DGS.
Screening
Screening of DGS depends on known family history and then approaching with genetic studies in individual cases.
Natural History, Complications, and Prognosis
Natural History
It is important to note that the broad spectrum of disease severity makes the evaluation of DGS particularly challenging. Cases involving significant cardiac, thymic, and craniofacial deficits are more easily recognizable than those lacking severe features.
Complications
Most patients with DGS may progress to develop severe recurrent infections, autoimmune diseases, and hematologic malignancies.
Prognosis
Prognosis is very poor, if left untreated, most patients die by 12 months of age.
Diagnosis
Diagnostic Criteria
History and Symptoms
A broad spectrum of disease severity exists, and suspicion of DGS from history and physical can prompt further evaluation. Although most cases get diagnosed in the prenatal and pediatric periods, diagnosis can also occur in adulthood.
Delay in motor development is a common presenting feature first recognized by parents who notice delays in rolling over, sitting up, or other infant milestones.
Characteristic signs and symptoms include heart defects that are often present from birth, an opening in the roof of the mouth (a cleft palate or other defect in the palate), autism, other learning disabilities, mild differences in facial features, and recurrent viral or fungal infections are common due to problems with the immune system‘s T-cell mediated response.
Physical Examination
A complete cardiopulmonary evaluation can reveal murmurs, cyanosis, clubbing, or edema consistent with aortic arch anomalies, conotruncal defects (e.g., tetralogy of Fallot, truncus arteriosus, pulmonary atresia with ventricular septal defect, transposition of the great vessels, interrupted aortic arch), or tricuspid atresia.
Recurrent sinopulmonary infections due to T cell deficiency as a result of thymic hypoplasia
Signs of hypocalcemia, including twitching and muscle spasm, may be evident as a result of parathyroid hypoplasia. Chvostek’s and Trousseau’s signs may be positive.
Delayed development, unusual behavior, or signs of psychiatric disorders may be observable.
Laboratory Findings
- Hypocalcemia (50%)(due to hypoparathyroidism)
- Growth hormone deficiency
Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Prevention
References
- ↑ McDonald-McGinn, Donna M. MS, CGC; Sullivan, Kathleen E. MD, PhD Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome), Medicine: January 2011 – Volume 90 – Issue 1 – p 1-18 doi: 10.1097/MD.0b013e3182060469
- ↑ McDonald-McGinn, Donna M. MS, CGC; Sullivan, Kathleen E. MD, PhD Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome), Medicine: January 2011 – Volume 90 – Issue 1 – p 1-18 doi: 10.1097/MD.0b013e3182060469
Historical Perspective
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayushi Jain, M.B.B.S[2]
Overview
Historical Perspective
Discovery
DGS characteristics were first described in 1828 but adequately reported later in 1965 by Dr. Angelo DiGeorge, as a clinical trial that included immunodeficiency, hypoparathyroidism, and congenital heart disease.[1]
- Harrington [2] first noted the association between thymic aplasia and DiGeorge syndrome in 1829 and later Lobdell[3] noted its association with congenital hypoparathyroidism in 1959.
- DiGeorge had evaluated 29 patients by 1979 and the next important publication on DGS was that of Conley et al[4] on the which described the spectrum of DGS. Conley’s series also noted both the association of DGS with CHARGE association and of DGS and holoprosencephaly/arhinencephaly.
- Conley et al[4] pointed out the association of DGS with conotruncal cardiac defects in 1979.
- In terms of pathogenesis and aetiology, Lammer and Opitz[5] reviewed various mechanisms in 1986. DGA can occur because of various chromosome abnormalities like mendelian disorders (including velocardiofacial syndrome (VCFS) and Zellweger syndrome), teratogenic exposure (alcohol, maternal diabetes, retinoids), and other associations (CHARGE associations and with Kallmann syndrome or with holoprosencephaly) (the latter two may be a spectrum of the same defect).
- Historically, DGS was grouped within a sphere of other syndromes such as Shprintzen-Goldberg syndrome, velocardiofacial syndrome, Cayler cardiofacial syndrome, Sedlackova syndrome, conotruncal anomaly face syndrome, and DGS, collectively called 22q11 deletion syndromes. They have the same genetic etiology but their varying phenotypes has has led to confusion in diagnosing patients with DGS, which causes potentially catastrophic delays in diagnosis.[6]
Landmark Events in the Development of Treatment Strategies
There have been no landmark events witnessed in the treatment strategy for DGS.
Impact on Cultural History
Famous Cases
The following are a few famous cases of [disease name]:
References
- ↑ McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JA, Zackai EH, Emanuel BS, Vermeesch JR, Morrow BE, Scambler PJ, Bassett AS. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015 Nov 19;1:15071.
- ↑ Harrington LH. Absence of the thymus gland. Lond Med Gaz 1929;3:314.
- ↑ Lobdell DH. Congenital absence of the parathyroid glands. Arch Pathol 1959;67:412-18.
- ↑ 4.0 4.1 Conley ME, Beckwith JB, Mancer JFK, Tenckhoff L. The spectrum of the DiGeorge syndrome. J7 Pediatr 1979;94:883-90.
- ↑ Lammer EJ, Opitz JM. The DiGeorge anomaly as a developmental field defect. Am J7 Med Genet Suppl 1986;2:1 13-27.
- ↑ Fomin AB, Pastorino AC, Kim CA, Pereira CA, Carneiro-Sampaio M, Abe-Jacob CM. DiGeorge Syndrome: a not so rare disease. Clinics (Sao Paulo). 2010;65(9):865-9.
Classification
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ayushi Jain, M.B.B.S[2]
Overview
Based on the subtype, DGS may be classified as either partial or complete.
Classification
There is no established system for the classification of DGS.
However, based on the severity, it may be classified as partial DGS and complete DGS.
Since symptoms of DiGeorge syndrome were variable and the underlying cause (deletions of 22q11.2) is responsible for other related/overlapping syndromes, using terms such as ‘complete’ and ‘partial’ DiGeorge syndrome is in reference to individual cases which had all the characteristic signs and symptoms (e.g., hypoparathyroidism, absent thymus, and heart disease) versus those with only some of them.[1]
References
- ↑ Akar NA, Adekile AD. Chromosome 22q11.2 deletion presenting with immune-mediated cytopenias, macrothrombocytopenia and platelet dysfunction. Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre. 2007 ;16(4):318-320. DOI: 10.1159/000102157.
Pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ayushi Jain, M.B.B.S[3]
Overview
The main factor leading to DGS is the deletion of 22q11.2, which encodes over 90 genes. Researchers have not yet identified all of the genes that contribute to the features of 22q11.2 deletion syndrome. They have determined that the loss of one particular gene on chromosome 22, TBX1, is probably responsible for many of the syndrome’s characteristic signs (such as heart defects, a cleft palate, distinctive facial features, and low calcium levels). A loss of this gene does not appear to cause learning disabilities, however. Additional genes in the deleted region are likely to contribute to the signs and symptoms of 22q11.2 deletion syndrome.
Pathophysiology
The main factor leading to DGS is the deletion of 22q11.2, which encodes over 90 genes. Because the signs and symptoms of 22q11.2 deletion syndrome are so varied, different groupings of features were once described as separate conditions. These included the velo-cardio-facial syndrome (also called Shprintzen’s syndrome), DiGeorge syndrome, hearing loss with craniofacial syndromes and conotruncal anomaly face syndrome, thymic hypoplasia, cleft palate, psychiatric disorders, and hypocalcaemia. The acronym CATCH-22 (C = cardiac defects, A = abnormal facies, T = thymic hypoplasia, C = cleft palate, H = hypocalcemia from parathyroid aplasia, 22 = microdeletions in chromosome 22) is sometimes used, although it is widely rejected because of the negative connotations with Catch-22 meaning a ‘no-win’ situation.
In addition, some children with the 22q11.2 deletion were diagnosed with Opitz G/BBB syndrome and Cayler cardiofacial syndrome. Once the genetic basis for these disorders was identified, doctors determined that they were all part of a single syndrome with many possible signs and symptoms. To avoid confusion, this condition is usually called 22q11.2 deletion syndrome, a description based on its underlying genetic cause.
Genetics
Most people with 22q11.2 deletion syndrome are missing about 3 million base pairs (the building blocks of DNA) on one copy of chromosome 22 in each cell. This region contains about 30 genes, but many of these genes have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region. This condition is often described as a contiguous gene deletion syndrome because a deletion in chromosome 22 leads to the loss of many genes.
CAUSE OF DELETION
The deletion is bracketed by low copy number repeats (LCRs).Four discrete blocks of LCRs are found in this region and each block is comprised of multiple repeats. 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.The asynchronous replication can be associated with mispairing of the LCR and subsequent unequal crossing over. 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.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.[1]
The syndrome is caused by genetic deletions (loss of a small part of the genetic material) found on the long arm of the 22nd chromosome. Some patients with similar clinical features may have deletions on the short arm of chromosome 10.
DiGeorge syndrome causes migration defects of neural crest-derived tissues, particularly affecting development of the third and fourth Branchial pouches (pharyngeal pouches). Also affected is the thymus gland; a mediastinal organ largely responsible for differentiation and induction of tolerance in T-cells. Impaired immune function results principally from this etiology.
Researchers have not yet identified all of the genes that contribute to the features of 22q11.2 deletion syndrome. They have determined that the loss of one particular gene on chromosome 22, TBX1, is probably responsible for many of the syndrome’s characteristic signs (such as heart defects, a cleft palate, distinctive facial features, and low calcium levels). A loss of this gene does not appear to cause learning disabilities, however. Additional genes in the deleted region are likely to contribute to the signs and symptoms of 22q11.2 deletion syndrome.
The 22q11.2 deletion syndrome can be inherited in an autosomal dominant manner. Almost all (about 93%) of cases have a de novo (new to the family) deletion of 22q11.2 but about 7% inherit the 22q11.2 deletion from a parent. Children of an individual with deletion 22q11.2 have a 50% chance of inheriting the 22q11.2 deletion. Prenatal testing, such as amniocentesis, is available for pregnancies determined to be at risk. Also pregnancies who have findings of congenital heart disease and/or cleft palate detected by ultrasound examination may be offered prenatal testing. Genetic counseling may be helpful for families who may have DiGeorge syndrome. Because most of the signs of this cluster of defects can also be inherited as autosomal recessive or x-linked traits, only genetic testing of both parents can determine with any certainty the likelihood these anomalies occurring in any subsequent children.
Associated Disorders
- Congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and persistent truncus arteriosus)
- Immune deficiency
- Renal anomalies (37%)
- Autoimmune disorders
- Autism and Autism spectrum disorders
Thymus, parathyroid glands and heart derive from the same primitive embryonic structure and that is why these three organs are dysfunctioned together in this disease. Affected patients (usually children) are prone to yeast infections.
References
- ↑ McDonald-McGinn, Donna M. MS, CGC; Sullivan, Kathleen E. MD, PhD Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome), Medicine: January 2011 – Volume 90 – Issue 1 – p 1-18 doi: 10.1097/MD.0b013e3182060469
]
Differentiating 22q11.2 deletion syndrome from other Diseases
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: : Ayushi Jain, M.B.B.S[2]
Overview
DGS must be differentiated from other diseases that cause similar clinical features and have a broad spectrum of presentation. All of the clinical findings associated with 22q11.2 deletion syndrome (22q11.2DS) can also occur as an isolated anomaly in an otherwise healthy individual. Genetic disorders and teratogenic exposures that may cause a clinical phenotype similar to 22q11.2DS are discussed in this section.
Differentiating [Disease name] from other Diseases
All of the clinical findings associated with 22q11.2 deletion syndrome (22q11.2DS) can also occur as an isolated anomaly in an otherwise healthy individual. Genetic disorders and teratogenic exposures that may cause a clinical phenotype similar to 22q11.2DS are discussed in this section. DGS must be differentiated from Smith-Lemli-Opitz syndrome, Oculo-auriculo vertebral (Goldenhar) syndrome (OAVS), Alagille syndrome, VATER association, and CHARGE syndrome.
Differentiating DGS from other diseases on the basis of overlapping features
| Differential Diagnosis | Clinical Manifestations Overlapping with DGS | ||
|---|---|---|---|
| Single Gene Disorders | |||
| Disorder | Gene Involved | Mode of Inheritance | |
| Smith-Lemli-Opitz syndrome | DHCR7 | AR | Polydactyly & cleft palate |
| Alagille syndrome | JAG1NOTCH2 | AD | Butterfly vertebrae, CHD, & posterior embryotoxon |
| CHARGE syndrome | CHD7 | AD | CHD, palatal anomalies, coloboma, choanal atresia, growth deficiency, ear anomalies / hearing loss, DDs, facial palsy, genitourinary anomalies, & immunodeficiency |
| Tetralogy of Fallot | TBX1 1 | AD | CHD, preauricular pits |
| Chromosome Disorders | – | – | |
| Deletion 10p13-p14 | – | cardiac defects, immune deficiency, hypoparathyroidism, cleft palate, developmental delay, microcephaly, and cryptorchidism | |
| Deletion 11q23-ter (Jacobsen syndrome) | – | – | microcephaly, micrognathia, low set ears, ocular manifestations, cardiac defects, hypospadias, cryptorchidism, and immune deficiency. |
| Other | – | – | |
| Disorders of unknown genetic etiology | – | – | |
| VACTERL association
(when congenital heart disease, vertebral, renal, and limb anomalies are present) |
– | – | VATER association is a diagnosis of exclusion without an established etiology to date |
| Oculoauriculovertebral (Goldenhar) syndrome (OAVS) (when ear anomalies, vertebral defects, heart disease, renal anomalies are present) | – | – | Ear anomalies, heart disease, Vertebral defects, renal anomalies. |
| Teratogenic exposures | – | – | A phenotype similar to 22q11.2DS can be associated with maternal diabetes and maternal retinoic acid exposure |
References
Causes
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ayushi Jain, M.B.B.S[2]
Overview
Most cases are linked to microdeletion of chromosome 22, at the long arm (q) at the 11.2 locus.Failure in embryologic development of the pharyngeal pouches, which is driven by TBX1, leads to absence or hypoplasia of the thymus and parathyroid glands.
Causes
Approximately 90% of DGS cases are due to deletion in chromosome 22, more specifically on the long arm (q) at the 11.2 locus (22q11.2). Most of these mutations arise de novo with no genetic abnormalities noted in the genome of the parents of children with DGS. Researchers have identified over 90 different genes at this locus, some of which they have studied in mouse models. T-box transcription factor 1 (TBX1) is the most studied gene , which correlates with severity of DGS such as defects in the development of the heart, thymus, and parathyroid glands of mouse models.
Failure in embryologic development of the pharyngeal pouches, which is driven by TBX1, leads to absence or hypoplasia of the thymus and parathyroid glands.
Mouse and zebrafish TBX1 knockout models have been studied to understand the embryologic basis of this disease. In mice, for instance, the absence of TBX1 causes severe pharyngeal, cardiac, thymic, and parathyroid defects as well as a behavioral disturbance.[1] Moreover, zebrafish knockouts have demonstrated defects in the thymus and pharyngeal arches as well as malformation of the ears and thymus.[2]
TBX1 also correlates with neuromicrovascular anomalies, which may be responsible for the behavioral and developmental abnormalities seen in DGS.[3][4]
References
- ↑ Zhang Z, Huynh T, Baldini A. Mesodermal expression of Tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development. Development. 2006 Sep;133(18):3587-95.
- ↑ Guner-Ataman B, González-Rosa JM, Shah HN, Butty VL, Jeffrey S, Abrial M, Boyer LA, Burns CG, Burns CE. Failed Progenitor Specification Underlies the Cardiopharyngeal Phenotypes in a Zebrafish Model of 22q11.2 Deletion Syndrome. Cell Rep. 2018 Jul 31;24(5):1342-1354.e5.
- ↑ Cioffi S, Martucciello S, Fulcoli FG, Bilio M, Ferrentino R, Nusco E, Illingworth E. Tbx1 regulates brain vascularization. Hum. Mol. Genet. 2014 Jan 01;23(1):78-89.
- ↑ Paylor R, Glaser B, Mupo A, Ataliotis P, Spencer C, Sobotka A, Sparks C, Choi CH, Oghalai J, Curran S, Murphy KC, Monks S, Williams N, O’Donovan MC, Owen MJ, Scambler PJ, Lindsay E. Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proc. Natl. Acad. Sci. U.S.A. 2006 May 16;103(20):7729-34.
Epidemiology and Demographics
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ayushi Jain, M.B.B.S[3]
Overview
The estimated prevalence has been cited in several studies as being 1:3000-1:6000 births.
Currently, the figures are 6%-10% of new cases are familial. Since survival with cardiac anomalies was low until the mid-1980s, the familial cases are expected to rise.
Epidemiology and Demographics
The estimated prevalence has been cited in several studies as being 1:3000-1:6000 births. 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. Since survival with cardiac anomalies was low until the mid-1980s, the familial cases are expected to rise.
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.
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.
References
Risk Factors
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ayushi Jain, M.B.B.S[2]
Overview
The only known risk factor is that of a family history of DGS.
Risk Factors
A detailed history may reveal :
- Family history of diagnosed or suspected DGS
- Abnormal genetic testing results of family members
References
Screening
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ayushi Jain, M.B.B.S[2]
Overview
Screening of DGS depends on known family history and then approaching with genetic studies in individual cases.
Screening
Indications of screening depends on the clinical presentation. 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.[1]
References
- ↑ https://emedicine.medscape.com/article/886526-workup#c7. Missing or empty
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Natural History, Complications and Prognosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayushi Jain, M.B.B.S[2]
Overview
It is important to note that the broad spectrum of disease severity makes the evaluation of DGS particularly challenging. Cases involving significant cardiac, thymic, and craniofacial deficits are more easily recognizable than those lacking severe features.
Most patients with DGS may progress to develop severe recurrent infections, autoimmune diseases, and hematologic malignancies.
Prognosis is very poor, if left untreated, most patients die by 12 months of age.
Natural History, Complications, and Prognosis
Natural History
- The symptoms of DGS usually develop in the first year itself and starts with symptoms such as delays in the achievement of developmental milestones.
- Other symptoms include :
- Behavioral disturbance
- Cyanosis, exercise intolerance, or symptoms
- Recurrent infections secondary to T-cell deficiency
- Speech difficulty
- Difficulty feeding and/or failure to thrive
- Muscle spasms, twitching, tetany, seizure
- Later in life, abnormal behavior in the setting of poor developmental history may be the chief presenting symptom of DGS.[1]
Complications
- Common complications of DGS include:
- Severe recurrent infections
- Autoimmune diseases
- Hematologic malignancies.
- Cardiac and craniofacial anomalies associated with DGS may require surgical repair. As with any surgical procedure, the possibility of complications, including bleeding, infection, and prolonged hospitalization, exists. These risks are particularly dangerous for DGS patients with significant immunocompromise. Consistent follow-up of patients with DGS is necessary to evaluate for these possible complications.
Prognosis
- Without treatment, prognosis is very poor, and most patients die by 12 months of age.Less than 1% of patients with 22q11.2 microdeletion have complete DGS, accounting for the very poor prognosis. n a study of 50 infants who received a thymic transplant for complete DGS, only 36 survived to two years.[2]
- Depending on the type of DGS, as complete or partial and the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor.
- Partial DGS is associated with the most favorable prognosis, but still not a defined prognosis. Some do not survive infance due to severe cardiac defects and many survive into adulthood.
References
- ↑ McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JA, Zackai EH, Emanuel BS, Vermeesch JR, Morrow BE, Scambler PJ, Bassett AS. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015 Nov 19;1:15071.
- ↑ Markert ML, Devlin BH, Chinn IK, McCarthy EA. Thymus transplantation in complete DiGeorge anomaly. Immunol. Res. 2009;44(1-3):61-70.
Diagnosis
Diagnosis
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Treatment
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