22q11.2 deletion syndrome
Conotruncal anomaly face syndrome
Cayler cardiofacial syndrome
Congenital thymic aplasia
DiGeorge 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.
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. The inheritance pattern is autosomal dominant and it has a prevalence estimated at 1:4000. The syndrome was described in 1968 by the pediatric endocrinologist Angelo DiGeorge. 22q11 deletion is also associated with truncus arteriosus and tetralogy of Fallot.
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. Disorders such as hypothyroidism and hypoparathyroidism or thrombocytopenia (low platelet levels), and psychiatric illnesses are common late-occurring features.
Microdeletions in chromosomal region 22q11.2 are associated with a 20 to 30-fold increased risk of schizophrenia. 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.
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:
Cardiac abnormality (especially tetralogy of Fallot)
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:
- Congenital heart disease (40% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and persistent truncus arteriosus)
- 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
- 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 cell numbers
- Seizures (with or without hypocalcemia)
- Skeletal abnormalities
- Psychiatric disorders
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.
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.
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.
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. Common problems include hypernasality, language delays, and speech sound errors.
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.
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.
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.
DiGeorge syndrome is caused by the deletion of a portion of chromosome 22. Each person has two copies of chromosome 22, one inherited from each parent.
If a person has DiGeorge syndrome, one copy of chromosome 22 is missing a segment that includes an estimated 30 to 40 genes. Many of these genes haven't been clearly identified and aren't well-understood. The region of chromosome 22 that's deleted in DiGeorge syndrome is known as 22q11.2.
The deletion of genes from chromosome 22 usually occurs as a random event in the father's sperm or in the mother's egg, or it may occur early during fetal development. Rarely, the deletion is an inherited condition passed to a child from a parent who also has deletions in chromosome 22 but may or may not have symptoms.
In some cases, DiGeorge syndrome may be passed from an affected parent to a child. People concerned about a family history of DiGeorge syndrome, or already have a child with DiGeorge syndrome, may want to consult a doctor who specializes in genetic disorders (geneticist) or a genetic counselor for help in planning future pregnancies.
The 22q11.2 deletion syndrome is diagnosed in individuals with a submicroscopic deletion of chromosome 22 detected by fluorescence in situ hybridization (FISH), BACs-on-Beads technology, Multiplex ligation-dependent probe amplification (MLPA) or array-comparative genomic hybridization (array-CGH). FISH is done on a blood sample: one DNA probe from the 22q11.2 chromosomal region is used at a time, while with BACs-on-Beads technology, multiple probes from the 22q11.2 region can be used simultaneously. In MLPA testing, various probes for selected regions of 22q11.2 are used to identify microdeletions, but any findings should be further confirmed by other techniques (FISH or array-CGH). Array-CGH is a technique of molecular karyotype where a large number of probes are embedded in a chip to screen the entire genome for deletions or duplications. Array-CGH can identify the extent of the microdeletion in 22q11.2 chromosomal region and characterize any missing genes, leading to a better evaluation of signs, symptoms, and prognosis of the syndrome. 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. Some cases of DiGeorge syndrome have defects in other chromosomes, notably a deletion in chromosome region 10p14. They may have variant deletions of DiGeorge syndrome that may be detectable on a research basis only or with other more advanced clinical testing method.
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. 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.