DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by the deletion of a small segment of chromosome 22.[7] While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent infections, developmental delay, learning problems and cleft palate.[7] Associated conditions include kidney problems, hearing loss and autoimmune disorders such as rheumatoid arthritis or Graves disease.[7]
DiGeorge syndromeOther namesDiGeorge anomaly,[1][2]velocardiofacial syndrome (VCFS),[3]Shprintzen syndrome,[4]conotruncal anomaly face syndrome (CTAF),[5] Takao syndrome,[6]Sedlackova syndrome,[7] Cayler cardiofacial syndrome,[7]CATCH22,[7] 22q11.2 deletion syndrome[7]
A child with DiGeorge syndromeSpecialtyMedical geneticsSymptomsVaried; commonly congenital heart problems, specific facial features, cleft palate[7]ComplicationsKidney problems, hearing loss, autoimmune disorders[7]CausesGenetic (typically new mutation)[7]Diagnostic methodBased on symptoms and genetic testing[5]Differential diagnosisSmith–Lemli–Opitz syndrome, Alagille syndrome, VACTERL, Oculo-auriculo-vertebral spectrum[5]TreatmentInvolves many healthcare specialties[5]PrognosisDepends on the specific symptoms[3]Frequency1 in 4,000[7]
DiGeorge syndrome is typically due to the deletion of 30 to 40 genes in the middle of chromosome 22 at a location known as 22q11.2.[3] About 90% of cases occur due to a new mutation during early development, while 10% are inherited from a person’s parents.[7] It is autosomal dominant, meaning that only one affected chromosome is needed for the condition to occur.[7] Diagnosis is suspected based on the symptoms and confirmed by genetic testing.[5]
Although there is no cure, treatment can improve symptoms.[3] This often includes a multidisciplinary approach with efforts to improve the function of the potentially many organ systems involved.[8] Long-term outcomes depend on the symptoms present and the severity of the heart and immune system problems.[3] With treatment, life expectancy may be normal.[9]
DiGeorge syndrome occurs in about 1 in 4,000 people.[7] The syndrome was first described in 1968 by American physician Angelo DiGeorge.[10][11] In late 1981, the underlying genetics were determined.[11]
Signs and symptomsEdit
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 responsethat in some patients is due to an absent or hypoplastic thymus. DiGeorge 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 defects 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.[12] Disorders such as hypothyroidism and hypoparathyroidism or thrombocytopenia (low platelet levels), and psychiatric illnesses are common late-occurring features.[13]
Microdeletions in chromosomal region 22q11.2 are associated with a 20 to 30-fold increased risk of schizophrenia.[14] Studies provide various rates of 22q11.2DS in schizophrenia, ranging from 0.5 to 2.0% and averaging about 1.0%, compared with the overall estimated 0.025% risk of the 22q11.2DS in the general population.[15]
Salient features can be summarized using the mnemonic CATCH-22 to describe 22q11.2DS, with the 22 signifying the chromosomal abnormality is found on the 22nd chromosome, as below:[16]
Cardiac abnormality (commonly interrupted aortic arch, truncus arteriosus and tetralogy of Fallot)
Abnormal facies
Thymic aplasia
Cleft palate
Hypocalcemia/hypoparathyroidism
Individuals 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:
Congenital heart disease (40% of individuals), particularly conotruncalmalformations (interrupted aortic arch(50%), persistent truncus arteriosus (34%), tetralogy of Fallot, and ventricular septal defect)
Cyanosis (bluish skin due to poor circulation of oxygen-rich blood)
Palatal abnormalities (50%), particularly velopharyngeal incompetence, submucosal cleft palate, and cleft palate; characteristic facial features (present in the majority of Caucasian individuals) including hypertelorism
Learning difficulties (90%), including cognitive deficits, attention deficit disorders[17]
Hypocalcemia (50%)(due to hypoparathyroidism)
Significant feeding problems (30%)
Renal anomalies (37%)
Hearing loss (both conductive and sensorineural) (hearing loss with craniofacial syndromes)
Laryngotracheoesophageal anomalies
Growth hormone deficiency
Autoimmune disorders
Immune disorders due to reduced T cellnumbers
Seizures (with or without hypocalcemia)
Skeletal abnormalities
Psychiatric disorders[17]
This syndrome is characterized by incomplete penetrance. Therefore, there is a marked variability in clinical expression between the different patients. This often makes early diagnosis difficult.[18]
Cognitive impairmentsEdit
Children with DiGeorge syndrome 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.[19]
Adults with DiGeorge syndrome are a specifically high-risk group for developing schizophrenia. About 30% have at least one incident of psychosis and about a quarter develop actual schizophrenia.[20]
Individuals with DiGeorge syndrome also have a higher risk of developing early onset Parkinson’s disease (PD). Diagnosis of Parkinson’s can be delayed by up to 10 years due to the use of antipsychotics, which can cause parkinsonian symptoms.[21][22]
Speech and languageEdit
Current research demonstrates a unique profile of speech and language impairments is associated with 22q11.2DS. 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.[23][24][25]
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.[23][24][26][27][28]
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.[24][27][28][29]
Articulation errors are commonly present in children with DiGeorge syndrome. These errors include a limited phonemic (speech sound) inventory and the use of compensatory articulation strategies resulting in reduced intelligibility. The phonemicinventory 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 inventoryand 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.[23][27]
DiagnosisEdit
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.
Brain computer tomography cuts of the person, demonstrating basal ganglia and periventricular calcification.[40]
Diagnosis of DiGeorge 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 karyotyping (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.[41] qPCR analysis is also quicker than FISH, which can have a turn around of 3 to 14 days.[12]
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.[42]
Genetic testing using BACs-on-Beads has been successful in detecting deletions consistent with 22q11.2DS during prenatal testing.[43][44] 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.[45]
Fewer than 5% of individuals with symptoms of DiGeorge syndrome have normal routine cytogenetic studies and negative FISH testing. In these cases, atypical deletions are the cause.[46] Some cases of 22q11.2 deletion syndrome have defects in other chromosomes, notably a deletion in chromosome region 10p14
TreatmentEdit
No cure is known for DiGeorge 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.[47] Thymus transplantation can be used to address absence of the thymus in the rare, so-called “complete” DiGeorge syndrome.[48] 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. Specialty clinics that provide multi-system care allow for individuals with DiGeorge syndrome to be evaluated for all of their health needs and allow for careful monitoring of the patients. An example of this type of system is the 22q Deletion Clinic at SickKids Hospital in Toronto, Canada, which provides children with 22q11 deletion syndrome ongoing support, medical care and information from a team of health care workers.[49]