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22q11.2 deletion syndrome

22q11.2 deletion syndrome, also known as Velocardiofacial Syndrome, DiGeorge Syndrome, conotruncal anomaly face syndrome, Congenital Thymic Aplasia, and Strong Syndrome is a disorder caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated q11.2 i.e., on the long arm of one of the pair of chromosomes 22. It has a prevalence estimated at 1:4000.

Presentation

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 defects in the palate, most commonly related to neuromuscular problems with closure (velo-pharyngeal insufficiency), learning disabilities, mild differences in facial features, and recurrent infections. Infections are common children due to problems with the immune system's T-cell mediated response that in a minority of patients is due to an absent or hypoplastic thymus. 22q11.2 deletion syndrome may be first spotted when an affected newborn has convulsions from hypocalcemia due to malfunctioning the parathyroid glands and low levels of parathyroid hormone (parathormone). Affected individuals may also have any other kind of birth defect including kidney abnormalities and significant feeding difficulties as babies. Autoimmune disorders such as hypothyroidism and hyperparathyroidism or thrombocytoperia (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% and averaging about 1%, compared with the overall estimated 0.025% risk of the 22q11.2 deletion syndrome in the general population.

Nomenclature

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, DiGeorge syndrome, and conotruncal anomaly face syndrome,

Symptoms

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

Congenital heart disease (40% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and persistent truncus arteriosus)
palatal abnormalities (50%), particularly velopharyngeal incompetence (VPI), submucosal cleft palate, and cleft palate; characteristic facial features (present in the majority of Caucasian individuals) including hypertelorism.
learning difficulties (90%) but broad range
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
seizures (without hypocalcemia)
skeletal abnormalities

Cause

The syndrome is caused by genetic deletions (loss of a small part of the genetic material) found on the long arm of one of the two 22nd chromosomes. Very rarely, patients with somewhat similar clinical features may have deletions on the short arm of chromosome 10.

The mechanism that causes all of the associated features of the syndrome is unknown. Some believe that 22q11.2 deletion syndrome may involve 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.

Treatment

There is no genetic treatment of 22q11.2 deletion syndrome. Most of the individual features are treatable however 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 is important that the immune problems are identified early as special precautions are required regarding blood transfusion and immunisation 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.

Diagnosis/testing

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 22q11.2 chromosomal region. 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 or with other more advanced clinical testing method.

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 45 genes, but some of these genes have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region.

Researchers have not yet identified 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 some of the syndrome's characteristic signs (such as heart defects) carrying only one copy 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 and genes outside the 22q11.2 region may also play a role.

The 22q11.2 deletion syndrome can be inherited ibut this is the case in the minority of newly diagnosed individuals. Only 5-10% have inherited the 22q11.2 deletion from a parents whereas about 90-95% of cases have a de novo (new to the family) deletion of 22q11.2. This is because the 22q11.2 region has a structure that makes it highly prone to rearragements during sperm for nation or egg formation. The deletion is about equally likely to occur when an egg is formed or when a sperm is formed. An individual with deletion 22q11.2 has a 50% (one in two) chance of passing 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 palate anomalies detected by ultrasound examination may be offered prenatal testing for 22q11.2 deletion syndrome. Genetic counseling is essenital for all families who have 22q11.2 deletion 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.

Epidemiology

22q11.2 deletion syndrome affects an estimated 1 in 4000 live births . This estimate is based on major birth defects and may be an underestimate. That is the condition may be more common because some people with the deletion have few signs and symptoms and may not have been diagnosed.

Cognitive and language problems

Cognitive Impairments

Children with 22q11.2 have a specific profile in neuropsychological tests. They usually have a borderline Full Scale IQ (55-85) with most individuals having higher scores in the verbal than the nonverbal domains. Cognitive functioning when processing information involving space and time show usually shows significant impairment and this generally slows the development of numerical and arithmetical knowledge and skills. Inattentiveness and problems with inhibition (often referred to using the label "executive function") generally shows considerable impairment. Familial transmission of the disease seems to result in worse cognitive impairments than the de novo cases, though this may be due to the level of cognitive stimulation that is available rather than direct genetic effects.

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.

Speech and Language

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.

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 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.

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 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.