DiGeorge syndrome

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22q11.2 deletion syndrome
File:Brain computer tomography cuts of the patient with 22q11.2 syndrome, demonstrating basal ganglia and periventricular calcification.jpg
Brain computer tomography cuts of the patient, demonstrating basal ganglia and periventricular calcification. From a case report by Tonelli et al., 2007[1]
Classification and external resources
Specialty Medical genetics
ICD-10 D82.1
ICD-9-CM 279.11, 758.32
OMIM 188400
DiseasesDB 3631
eMedicine med/567 ped/589derm/716
Patient UK DiGeorge syndrome
MeSH D004062
GeneReviews
Orphanet 567
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DiGeorge syndrome[2] is also known as 22q11.2 deletion syndrome,[3]DiGeorge anomaly,[4][5] velocardiofacial syndrome (VCFS), Shprintzen syndrome,[6] conotruncal anomaly face syndrome (CTAF) or Takao syndrome,[7] Sedlackova syndrome, Cayler cardiofacial syndrome,[8] Strong syndrome, congenital thymic aplasia, and thymic hypoplasia. This syndrome is caused by the deletion of a small piece of chromosome 22. As such, it is recommended that the name "22q11.2 deletion syndrome (22q11.2DS)" be used.[9][10]

22q11.2DS is the most common microdeletion syndrome characterized by low copy repeats and the deletion occurs near the middle of the chromosome at a location designated 22q11.2—signifying its location on the long arm of one of the pair of chromosomes 22, on region 1, band 1, sub-band 2.[11] The inheritance pattern is autosomal dominant and it has a prevalence estimated at 1:4000.[12] The syndrome was described in 1968 by the pediatric endocrinologist Angelo DiGeorge.[13][14] 22q11 deletion is also associated with truncus arteriosus and tetralogy of Fallot.[15]

Signs and symptoms

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 may include birth defects such as congenital heart disease, defects in the palate, most commonly related to neuromuscular problems with closure (velopharyngeal insufficiency), learning disabilities, mild differences in facial features, and recurrent infections. Infections are common in children due to problems with the immune system's T-cell-mediated response that in some patients is due to an absent or hypoplastic thymus. 22q11.2 deletion syndrome may be first spotted when an affected newborn has heart defects or convulsions from hypocalcemia due to malfunctioning parathyroid glands and low levels of parathyroid hormone (parathormone). Affected individuals may also have other kinds of birth defect including kidney abnormalities and significant feeding difficulties as babies. Gastrointestinal issues are also very common in this patient population. Digestive motility issues may result in constipation.[16] Disorders such as hypothyroidism and hypoparathyroidism or thrombocytopenia (low platelet levels), and psychiatric illnesses are common late-occurring features.[17]

Microdeletions in chromosomal region 22q11.2 are associated with a 20 to 30-fold increased risk of schizophrenia.[18] Studies provide various rates of 22q11.2 deletion syndrome in schizophrenia, ranging from 0.5 to 2.0% and averaging about 1.0%, compared with the overall estimated 0.025% risk of the 22q11.2 deletion syndrome in the general population.[19]

Salient features can be summarized using the mnemonic CATCH-22 to describe DiGeorge syndrome, with the 22 to remind one the chromosomal abnormality is found on the 22 chromosome, as below:[20]

Cardiac abnormality (especially tetralogy of Fallot)
Abnormal facies
Thymic aplasia
Cleft palate
Hypocalcemia/Hypoparathyroidism

Individuals with a 22q11.2 deletion can have many possible features, ranging in number of associated features and from the mild to the very serious. Symptoms shown to be common include:

This syndrome is characterized by incomplete penetrance and therefore there is a marked variability in clinical expression between the different patients. This often makes early diagnosis difficult.[3]

Cognitive impairments

Children with 22q11.2 have a specific profile in neuropsychological tests. They usually have a below-borderline normal IQ, with most individuals having higher scores in the verbal than the nonverbal domains. Some are able to attend normal schools, while others are home-schooled or in special classes.The severity of hypocalcemia early in childhood is associated with autism-like behavioral difficulties.[22]

Adults with DiGeorge syndrome have a specifically high-risk group for developing schizophrenia. About 30% have at least one incident of psychosis and about a quarter develop actual schizophrenia.[23]

Individuals with 22q11.2DS also have a higher risk of developing early onset Parkinson's disease (PD). Diagnosis of PD in 22q11.2DS patients can be delayed by up to 10 years due to the use of antipsychotics, which can cause parkinsonian symptoms.[24]

Speech and language

Current research demonstrates a unique profile of speech and language impairments is associated with 22q11.2 deletion syndrome. Children often perform lower on speech and language evaluations in comparison to their nonverbal IQ scores.[contradictory] Common problems include hypernasality, language delays, and speech sound errors.[25][26][27]

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 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.[25][26][28][29][30]

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 not verbal 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.[26][29][30][31]

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 oral cavity such as: /p/, /w/, /m/, /n/, and glottal stops. Sound made in the middle of the mouth are completely absent. Compensatory articulation errors made by this population of children include: glottal stops, 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.[25][29]

Genetics

22q11.2 deletion syndrome is inherited in an autosomal dominant pattern.

DiGeorge Syndrome is caused by a hemizygous deletion of part of the long arm (q) of chromosome 22, region 1, band 1, sub-band 2 (22q11.2). Approximately 80-90% of patients have a deletion of 3Mb and 8% have a deletion of 1.5Mb.[32][33] The number of genes affected by the deletion has been cited as approximately 30 to 50.[34][35] Very rarely, patients with somewhat similar clinical features may have deletions on the short arm of chromosome 10.[36] The disorder has an autosomal dominant inheritance pattern. A French study of 749 people diagnosed between 1995 and 2013 found that the mutation was inherited in 15% of patients, of which 85.5% was from the mother.[37] Other studies have found inheritance rates of 6-10%. The majority cases are a result of a de novo (new to the family) deletion.[38] This is because the 22q11 reagon has a structure that makes it highly prone to rearrangements during sperm or egg formation.[39]

The exact mechanism that causes all of the associated features of the syndrome is unknown.[32] Of the 30-50 genes in the deleted region, a number have been identified as possibly playing a role in the development of some of the signs and symptoms.

TBX1

Haploinsufficiency of the TBX1 gene (T-box transcription factor TBX1) is thought to be the cause of some of the symptoms observed. Point mutations in this gene have also been observed in individuals with DiGeorge syndrome.[32] TBX1 is part of the T-box family of genes which have an important role in tissue and organ formation during embryonic development and it may have a role in the regulation of differentiation of post migration neural crest cells. The neural crest forms many of the structures affected in DiGeorge Syndrome, including the skull bones, mesenchyme of the face and palate, the outflow tract of the heart, and the thymus and parathyroid stroma. When there is a loss of expression of FGF18 during the development of the pharyngeal arches, neural crest cell death is seen. Although neither FGF18 or TBX1 are expressed in the neural crest cells, TBX1 might have a role in the regulation of FGF18 expression, ensuring that the differentiation of the these cells in the pharyngeal region is correct. Therefore, dysfunction of TBX1 may be responsible for some of the symptoms in DiGeorge Syndrome.[33]

Parkinson's disease genes

22q11.2DS has been associated with a higher risk of early onset Parkinson's disease (PD). The neuropathology seen is similar to LRRK2-associated PD. None of the genes affected in individuals with 22q11.2DS have previously been linked to PD but there are a number that are likely candidates. These include DGCR8 which is important for biogenesis of brain mircoDNA, SRPT5 which encodes a protein that interacts with the PARK2 protein, COMT which is involved in regulating dopamine levels, and microRNA miR-185 which is thought to target known PD loci LRRK2.[24]

Diagnosis

File:Fish analysis di george syndrome.jpg
Result of FISH analysis using LSI probe (TUPLE 1) from DiGeorge/velocardiofacial syndrome critical region. TUPLE 1 (HIRA) probe was labeled in Spectrum Orange and Arylsulfatase A (ARSA) in Spectrum Green as control. Absence of the orange signal indicates deletion of the TUPLE 1 locus at 22q11.2.

Diagnosis of 22q11.2 deletion syndrome can be difficult due to the number of potential symptoms and the variation in phenotypes between individuals. It is suspected in patients with one or more signs of the deletion. In these cases a diagnosis of 22q11.2DS is confirmed by observation of a deletion of part of the long arm (q) of chromosome 22, region 1, band 1, sub-band 2. Genetic analysis is normally performed using fluorescence in situ hybridization (FISH), which is able to detect microdeletions that standard keryotyping (e.g. G-banding) miss. Newer methods of analysis include Multiplex ligation-dependent probe amplification assay (MLPA) and quantitative polymerase chain reaction (qPCR), both of which can detect atypical deletions in 22q11.2 that are not detected by FISH.[40] qPCR analysis is also quicker than FISH, which can have a turn around of 3 to 14 days.[38] A 2008 study of a new high-definition MLPA probe developed to detect copy number variation at 37 points on chromosome 22q found it to be as reliable as FISH in detecting normal 22q11.2 deletions. It was also able to detect smaller atypical deletions that are easily missed using FISH. These factors, along with the lower expense and easier testing mean that this MLPA probe could replace FISH in clinical testing.[41]

Genetic testing using BACs-on-Beads has been successful in detecting deletions consistent with 22q11.2DS during prenatal testing.[42][43] Array-comparative genomic hybridization (array-CGH) uses a large number of probes embossed in a chip to screen the entire genome for deletions or duplications. It can be used in post and pre-natal diagnosis of 22q11.2.[44]

Fewer than 5% of individuals with clinical symptoms of the 22q11.2 deletion syndrome have normal routine cytogenetic studies and negative FISH testing. In these cases atypical deletions are the cause.[45] Some cases of DiGeorge syndrome have defects in other chromosomes, notably a deletion in chromosome region 10p14.[36]

Treatment

No cure is known for 22q11.2 deletion syndrome. Certain individual features are treatable using standard treatments. The key is to identify each of the associated features and manage each using the best available treatments.

For example, in children, it is important that the immune problems are identified early, as special precautions are required regarding blood transfusion and immunization with live vaccines. Thymus transplantation can be used to address absence of the thymus in the rare, so-called "complete" DiGeorge syndrome.[46] Bacterial infections are treated with antibiotics. Cardiac surgery is often required for congenital heart abnormalities. Hypoparathyroidism causing hypocalcaemia often requires lifelong vitamin D and calcium supplements.

Epidemiology

22q11.2 deletion syndrome was estimated to affect between one in 2000 and one in 4000 live births.[12] This estimate is based on major birth defects and may be an underestimate, because some individuals with the deletion have few symptoms and may not have been formally diagnosed. It is one of the most common causes of mental retardation due to a genetic deletion syndrome.[47]

The prevalence of 22q11.2DS has been expected to rise because of multiple reasons: (1) Thanks to surgical and medical advances, an increasing number of people are surviving heart defects associated with the syndrome. These individuals are in turn having children. The chances of a 22q11.2DS patient having an affected child is 50% for each pregnancy; (2) Parents who have affected children, but who were unaware of their own genetic conditions, are now being diagnosed as genetic testing become available; (3) Molecular genetics techniques such as FISH (fluorescence in situ hybridization) have limitations and have not been able to detect all 22q11.2 deletions. Newer technologies have been able to detect these atypical deletions.[48]

Recently, the syndrome has been estimated to affect up to one in 2000 live births.[49] Testing for 22q11.2DS in over 9500 pregnancies revealed a prevalence rate of 1/992.[50]

Nomenclature

The signs and symptoms of 22q11.2 deletion syndrome are so varied that different groupings of its features were once regarded as separate conditions. These original classifications included velocardiofacial syndrome, Shprintzen syndrome, DiGeorge sequence/syndrome, Sedlackova syndrome, and conotruncal anomaly face syndrome. All are now understood to be presentations of a single syndrome.

ICD-10 2015 version mentions 22q11.2DS using two codes: D82.1 (Di George syndrome)[51] and Q93.81 (Velo-cardio-facial syndrome).[52] The ICD-11 Beta Draft discusses the syndrome under “LD50.P1 CATCH 22 phenotype".[52] However, since this syndrome is caused by the deletion of a small piece of chromosome 22, it is recommended that the name "22q11.2 deletion syndrome (22q11.2DS)" be used.[9][10]

See also

References

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  13. ↑ DiGeorge AM. Congenital absence of the thymus and its immunologic consequences: concurrence with congenital hypoparathyroidism. IV(1). White Plains, NY: March of Dimes-Birth Defects Foundation; 1968:116-21
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This article incorporates public domain text from The U.S. National Library of Medicine

External links

Media related to DiGeorge Syndrome at Wikimedia Commons

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