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| {{Infobox_Disease | | | {{Infobox_Disease | |
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| OMIM = 188400 | | | OMIM = 188400 | |
| MedlinePlus = | | | MedlinePlus = | |
| eMedicineSubj = med |
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| eMedicineTopic = 567 |
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| eMedicine_mult = {{eMedicine2|ped|589}} {{eMedicine2|derm|716}} |
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| MeshID = D004062 | | | MeshID = D004062 | |
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| {{SI}} | | {{22q11.2 deletion syndrome}} |
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| {{editor help}} | | {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}} {{Ajane}} |
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| ==Overview==
| | {{SK}} DiGeorge syndrome; Velocardiofacial syndrome; Di George syndrome; Strong syndrome; third and fourth pharyngeal arch syndrome of Di George; CATCH phenotype; conotruncal anomaly face syndrome |
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| '''22q11.2 deletion syndrome''', also known as Velocardiofacial Syndrome, Di George Syndrome and Strong Syndrome is a disorder caused by the deletion of a small piece of [[chromosome 22 (human)|chromosome 22]]. The deletion occurs near the middle of the [[chromosome]] at a location designated q11.2. It has a prevalence estimated at 1:4000.<ref name="pmid14736631">{{cite journal |author=Oskarsdóttir S, Vujic M, Fasth A |title=Incidence and prevalence of the 22q11 deletion syndrome: a population-based study in Western Sweden |journal=Arch. Dis. Child. |volume=89 |issue=2 |pages=148-51 |year=2004 |pmid=14736631 |doi=}}</ref>
| | ==[[22q11.2 deletion syndrome overview|Overview]]== |
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| ==Presentation== | | ==[[22q11.2 deletion syndrome historical perspective|Historical Perspective]]== |
| The features of this syndrome vary widely, even among members of the same family, and affect many parts of the body. 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 disability|learning disabilities]], mild differences in facial features, and recurrent viral or fungal [[infection]]s are common due to problems with the [[immune system]]'s T-cell mediated response. DiGeorge syndrome is often first spotted when the affected newborn begins convulsing from hypocalcemia due to an absence of parathyroid and parathyroid hormone. Affected individuals may also have kidney abnormalities, significant feeding difficulties, [[autoimmune disorder]]s such as [[rheumatoid arthritis]], and an increased risk of developing mental illnesses.<!--
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| --><ref name="Bebbane_2006_psychosis">{{cite journal |author=Debbané M, Glaser B, David MK, Feinstein C, Eliez S |title=Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: Neuropsychological and behavioral implications |journal=Schizophr. Res. |volume=84 |issue=2-3 |pages=187-93 |year=2006 |pmid=16545541 |doi=10.1016/j.schres.2006.01.019}}</ref><!--
| | ==[[22q11.2 deletion syndrome classification|Classification]]== |
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| --> Microdeletions in chromosomal region 22q11 are associated with a roughly 30-fold increased risk of [[schizophrenia]], <!--
| | ==[[22q11.2 deletion syndrome pathophysiology|Pathophysiology]]== |
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| --><ref name="Horowitz_2005_SCHZ">{{cite journal |author=Bassett AS, Chow EW, AbdelMalik P, Gheorghiu M, Husted J, Weksberg R |title=The schizophrenia phenotype in 22q11 deletion syndrome |journal=Am J Psychiatry |volume=160 |issue=9 |pages=1580-6 |year=2003 |pmid=12944331 |doi=}}</ref><!--
| | ==[[22q11.2 deletion syndrome differential diagnosis|Differentiating 22q11.2 deletion syndrome from other Diseases]]== |
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| --> and are frequently detected in schizophrenic patients. Different studies provide different occurrence rates, ranging from 0.5 to 3%, compared with the overall 0.025% risk of the 22q11 deletion syndrome in the general population.<!--
| | ==[[22q11.2 deletion syndrome causes|Causes]]== |
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| --><ref name="Horowitz_2005_survey_SCHZ">{{cite journal |author=Horowitz A, Shifman S, Rivlin N, Pisanté A, Darvasi A |title=A survey of the 22q11 microdeletion in a large cohort of schizophrenia patients |journal=Schizophr. Res. |volume=73 |issue=2-3 |pages=263-7 |year=2005 |pmid=15653270 |doi=10.1016/j.schres.2004.02.008}}</ref><!--
| | ==[[22q11.2 deletion syndrome epidemiology and demographics|Epidemiology and Demographics]]== |
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| | ==[[22q11.2 deletion syndrome risk factors|Risk Factors]]== |
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| ==Nomenclature== | | ==[[22q11.2 deletion syndrome screening|Screening]]== |
| 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 (logic)|Catch-22]] meaning a 'no-win' situation.
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| 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.
| | ==[[22q11.2 deletion syndrome natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| ==Symptoms== | | ==Diagnosis== |
| Individuals with a 22q11 deletion can suffer from a range of over 200 possible symptoms, ranging from the mild to the very serious. Possible symptoms are:
| | [[22q11.2 deletion syndrome history and symptoms|History and Symptoms ]] | [[ 22q11.2 deletion syndrome physical examination|Physical Examination]] | [[22q11.2 deletion syndrome laboratory findings|Laboratory Findings]] | [[22q11.2 deletion syndrome electrocardiogram|Electrocardiogram]] | [[22q11.2 deletion syndrome chest x ray|Chest X Ray]] | [[22q11.2 deletion syndrome CT|CT ]] | [[22q11.2 deletion syndrome MRI|MRI]] | [[22q11.2 deletion syndrome echocardiography|Echocardiography]] | [[22q11.2 deletion syndrome other imaging findings|Other Imaging Findings]] | [[22q11.2 deletion syndrome other diagnostic studies|Other Diagnostic Studies]] |
| * [[Congenital heart disease]] (74% of individuals), particularly conotruncal malformations ([[tetralogy of Fallot]], [[interrupted aortic arch]], [[ventricular septal defect]], and [[persistent truncus arteriosus]])
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| * [[palatal]] abnormalities (69%), particularly [[velopharyngeal incompetence]] (VPI), submucosal [[cleft palate]], and [[cleft palate]]; characteristic facial features (present in the majority of Caucasian individuals) including [[hypertelorism]].
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| * [[learning difficulties]] (70-90%)
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| * an [[immune deficiency]] regardless of their clinical presentation (77%)
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| * [[hypocalcemia]] (50%)(due to hypoparathyroidism)
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| * significant feeding problems (30%)
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| * [[renal]] anomalies (37%)
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| * [[hearing impairment|hearing loss]] (both [[conductive]] and [[sensorineural]]) ([[Hearing loss with craniofacial syndromes]])
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| * laryngotracheoesophageal anomalies
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| * [[growth hormone]] deficiency
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| * [[autoimmune disorders]]
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| * [[seizures]] (without [[hypocalcemia]])
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| * [[skeletal]] abnormalities
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| * [[Autism]] and [[Autism spectrum disorders]]
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| [[Thymus]], [[parathyroid gland]]s 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]].
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| ==Cause==
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| 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.
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| 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 aetiology.
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| ==Treatment== | | ==Treatment== |
| Although genetic transplantation methods are currently being developed by researchers, there is yet no genetic treatment of this disease.
| | [[22q11.2 deletion syndrome medical therapy|Medical Therapy]] | [[22q11.2 deletion syndrome surgery |Surgery]] | [[22q11.2 deletion syndrome primary prevention|Primary Prevention]] | [[22q11.2 deletion syndrome secondary prevention|Secondary Prevention]] | [[22q11.2 deletion syndrome cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[22q11.2 deletion syndrome future or investigational therapies|Future or Investigational Therapies]] |
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| It is important that the immune problems are identified early as special precautions are required regarding blood transfusion and immunisation with live vaccines.
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| Treatment is largely symptomatic, [[infections]] are treated with [[antibiotics]], and these patients may undergo [[cardiac surgery]] for their heart abnormalities. [[Hypoparathyroidism]] causing hypocalcaemia is often transient, but may require lifelong vitamin D treatment.
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| Thymus transplantation can be used to address absence of the thymus in complete DiGeorge syndrome.<ref>{{cite journal |author=Markert ML, Devlin BH, Alexieff MJ, ''et al'' |title=Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants |journal=Blood |volume=109 |issue=10 |pages=4539-47 |year=2007 |pmid=17284531 |doi=10.1182/blood-2006-10-048652}}</ref>
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| ==Diagnosis/testing==
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| The 22q11.2 deletion syndrome is diagnosed in individuals with a submicroscopic deletion of [[chromosome]] 22 detected by [[fluorescence in situ hybridization]] (FISH) using DNA probes from the DiGeorge chromosomal region (DGCR). Such [[genetic testing]] is widely available for the clinical and [[prenatal testing]] of the 22q11.2 deletion syndrome. Fewer than 5% of individuals with clinical symptoms of the 22q11.2 deletion syndrome have normal routine cytogenetic studies and negative FISH testing. They may have variant deletions of DiGeorge syndrome that may be detectable on a research basis only.
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| ==Genetics==
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| [[Image:Autodominant.jpg|thumb|left|22q11.2 deletion syndrome is inherited in an [[autosomal dominant]] pattern.]]
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| Most people with 22q11.2 deletion syndrome are missing about 3 million [[base pair]]s (the building blocks of DNA) on one copy of [[chromosome 22 (human)|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.
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| 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.
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| 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.
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| ==Epidemiology==
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| 22q11.2 deletion syndrome affects an estimated 1 in 4000 live births <ref name="pmid14736631"/>. The condition may be more common, however, because some people with the deletion have few signs and symptoms and may not have been diagnosed. | |
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| ==Cognitive and language problems==
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| ===Cognitive deficits===
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| Children with 22q11.2 have a specific profile in neuropsychological tests. They usually have a low IQ (50-80) but with better verbal than procedural functions. Especially big problems are usually within arithmetic and executive skills. Familial transmission of the disease seems to result in worse cognitive impairments than the de novo cases. It has been speculated that the observed cognitive problems arise from visuo-spatial problems.
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| Noteworthy is that these patients are a specifically high-risk group for developing schizophrenia. 30% have at least one incident of [[psychosis]] and about a quarter develop actual [[schizophrenia]].<ref>{{cite journal |author=Zinkstok J, van Amelsvoort T |title=Neuropsychological profile and neuroimaging in patients with 22Q11.2 Deletion Syndrome: a review |journal=Child Neuropsychol |volume=11 |issue=1 |pages=21-37 |year=2005 |pmid=15823981 |doi=10.1080/09297040590911194}}</ref>
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| ===Speech and Language===
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| Current research demonstrates there is a unique profile of speech and language impairments associated with 22q11.2 deletion syndrome. Children often perform lower on speech and language evaluations in comparison to their nonverbal IQ scores. Common problems include hypernasality, language delays, and speech sound errors.<ref name="Dantonio">{{cite journal |author=D'Antonio LL, Scherer NJ, Miller LL, Kalbfleisch JH, Bartley JA |title=Analysis of speech characteristics in children with velocardiofacial syndrome (VCFS) and children with phenotypic overlap without VCFS |journal=Cleft Palate Craniofac. J. |volume=38 |issue=5 |pages=455-67 |year=2001 |pmid=11522167}}</ref><ref name="Scherer1999">{{cite journal |author=Scherer NJ, D'Antonio LL, Kalbfleisch JH |title=Early speech and language development in children with velocardiofacial syndrome |journal=Am. J. Med. Genet. |volume=88 |issue=6 |pages=714-23 |year=1999 |pmid=10581495}}</ref><ref name="Scherer2001">{{cite journal |author=Scherer NJ, D'Antonio LL, Rodgers JR |title=Profiles of communication disorder in children with velocardiofacial syndrome: comparison to children with Down syndrome |journal=Genet. Med. |volume=3 |issue=1 |pages=72-8 |year=2001 |pmid=11339384 |doi=}}</ref>
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| Hypernasality occurs when air escapes through the nose during the production of oral speech sounds resulting in reduced [[intelligibility]]. This is a common characteristic in the speech and language profile because 69% of children have [[palatal]] abnormalities. If the structure of the soft palate [[Soft palate|velum]] is such that it does not stop the flow of air from going up to the [[nasal cavity]], it will cause hypernasal speech. This phenomenon is referred as [[velopharyngeal inadequacy]] VPI. Hearing loss can also contribute to increased hypernasality because children with hearing impairments can have difficulty self monitoring their oral speech output. The treatment options available for VPI include prosthesis and surgery. <ref name="Dantonio"> </ref>
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| <ref name="Eliez">{{cite journal |author=Eliez S, Palacio-Espasa F, Spira A, ''et al'' |title=Young children with Velo-Cardio-Facial syndrome (CATCH-22). Psychological and language phenotypes |journal=Eur Child Adolesc Psychiatry |volume=9 |issue=2 |pages=109-14 |year=2000 |pmid=10926060 |doi=}}</ref><ref name="Robin">{{cite journal |author=Robin NH, Shprintzen RJ |title=Defining the clinical spectrum of deletion 22q11.2 |journal=J. Pediatr. |volume=147 |issue=1 |pages=90-6 |year=2005 |pmid=16027702 |doi=10.1016/j.jpeds.2005.03.007}}</ref><ref name="Scherer1999"> </ref><ref name="Solot">{{cite journal |author=Solot CB, Knightly C, Handler SD, ''et al'' |title=Communication disorders in the 22Q11.2 microdeletion syndrome |journal=J Commun Disord |volume=33 |issue=3 |pages=187-203; quiz 203-4 |year=2000 |pmid=10907715 |doi=10.1016/S0021-9924(00)00018-6}}</ref>
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| Difficulties acquiring vocabulary and formulating spoken language (expressive language deficits) at the onset of language development are also part of the speech and language profile associated with the 22q11.2 deletion. Vocabulary acquisition is often severely delayed for preschool age children. In some recent studies, children had a severely limited vocabulary or were still nonverbal at 2-3 years of age. School age children do make progress with expressive language as they mature, but many continue to have delays and demonstrate difficulty when presented with language tasks such as verbally recalling narratives and producing longer and more complex sentences. Receptive language, which is the ability to comprehend, retain, or process spoken language, can also be impaired although not usually with the same severity as expressive language impairments.
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| <ref name="Persson">{{cite journal |author=Persson C, Niklasson L, Oskarsdóttir S, Johansson S, Jönsson R, Söderpalm E |title=Language skills in 5-8-year-old children with 22q11 deletion syndrome |journal=Int J Lang Commun Disord |volume=41 |issue=3 |pages=313-33 |year=2006 |pmid=16702096 |doi=10.1080/13682820500361497}}</ref><ref name="Robin"> </ref><ref name="Scherer1999"> </ref><ref name="Solot"> </ref>
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| [[Articulation]] errors are commonly present in children with 22q11.2 deletion syndrome. These errors include a limited phonemic (speech sound) inventory and the use of compensatory articulation strategies resulting in reduced intelligibility. The phonemic inventory typically produced consists of sounds made in the front or back of the vocal tract such as: /p/, /w/, /j/, /m/, /n/, and glottal stops. Mid vocal tract sounds are completely absent. Compensatory articulation errors made by this population of children include: [[glottal stop]]s, nasal substitutions, pharyngeal fricatives, linguapalatal sibilants, reduced pressure on consonant sounds, or a combination of these symptoms. Of these errors, glottal stops have the highest frequency of occurrence. It is reasoned that a limited phonemic inventory and the use of compensatory articulation strategies is present due to the structural abnormalities of the palate. The speech impairments exhibited by this population are more severe during the younger ages and show a trend of gradual improvement as the child matures. <ref name="Dantonio"> </ref><ref name="Robin"> </ref>
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| == See also ==
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| * [[Asymmetric crying facies]]
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| ==References==
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| {{Reflist|2}}
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| ''This article incorporates public domain text from [http://ghr.nlm.nih.gov The U.S. National Library of Medicine]''
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| ==External links==
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| * [http://www.genetests.org/profiles/22q11deletion GeneReviews: 22q11.2 deletion syndrome]
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| * [http://timesonline.typepad.com/india_knight/ India Knight's blog about children with special needs. Her daughter suffers from 22q11.2 Deletion Syndrome]
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| * [http://www.vcfsef.org/index.html VCFS Educational Foundation, Inc.]
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| * [http://www.chop.edu/consumer/jsp/division/generic.jsp?id=74634 Children's Hospital of Philadelphia]
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| * [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.150 NIH]
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| * [http://www.maxappeal.org.uk MaxAppeal]
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| * [http://www.22q.org International 22q11.2 Deletion Syndrome Foundation]
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| * [http://www.vcfs.com.ar/index.html Asoc. Familias 22q11 DS/VCFS]
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| {{Immune disorders}}
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| {{Chromosomal abnormalities}}
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| {{SIB}}
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| [[Category:Genetic disorders]]
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| [[Category:Syndromes]]
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| [[Category:Immune system disorders]]
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| [[de:Mikrodeletionsyndrom 22q11]]
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| [[es:Síndrome de DiGeorge]]
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| [[fr:Microdélétion 22q11]]
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| [[id:Sindrom delesi 22q11]]
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| [[it:Sindrome da delezione 22q11]]
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| [[nl:Syndroom van DiGeorge]]
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| [[pl:Zespół Di George'a]]
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| [[ru:Синдром Ди Джоржи]]
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| [[fi:Catch 22]]
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| [[sv:22q11-deletionsyndromet]]
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