22q11.2 Deletion Syndrome
Several overlapping syndromes are included in the 22q11.2 deletion syndrome. These include:
- DiGeorge syndrome
- Velocardiofacial syndrome
- Conotruncal anomaly face syndrome
- Some cases of autosomal dominant Opitz G/BBB syndrome
- Sedlackova syndrome
- Cayler cardiofacial syndrome.
Their common genetic cause is a microdeletion (a very small piece of DNA is missing) from the long arm of chromosome 22. All of these conditions have significant overlap in their features and will be treated as a single condition in this brief review. This chromosome deletion is the most common deletion in human beings.
22q11.2 Deletion Syndrome is a contiguous gene deletion syndrome. Contiguous genes are a group of genes that are situated close together along a stretch of a chromosome (a structure in cells made up of DNA and proteins that carries many genes). If this section of the DNA is missing, many genes can be missing which usually causes functional and developmental changes for the person who carries it.
The way 22q11.2 deletion syndrome affects each person who has it can be very different, even when it runs in families. The presence of any one feature (symptom) of the syndrome does not necessarily mean there will be any other feature of the syndrome. So, the approach to treatment and management of any child with 22q11.2 deletion syndrome must be individualized, to treat their specific features. Most of the time (90%), 22q11.2 deletion syndrome is a one-time event which means that the chances of other family members having or inheriting it is small.
Chromosome 22q11.2 deletion syndrome occurs in approximately 1 out of every 4000 live births and in most cases the patient is the first to have the condition in the family. However, because the number of features and the level of severity can be so different in each person who has it, many investigators believe that the condition is likely more common than these estimates suggest.
22q11.2 deletion syndrome is the second most common cause of developmental delay and major congenital (present at birth) heart disease after Down syndrome. It accounts for approximately 2.4% of people with developmental disabilities and approximately 10% to 15% of people with Tetralogy of Fallot (a type of heart defect). Males and females of all ethnic backgrounds are affected in equal numbers.
Common Associated Conditions
Children with 22q11.2 deletion syndrome often have a subset some or all of the following features.
- About three quarters (74%) of the time, congenital heart disease will be present. Most commonly, these congenital heart defects are conotruncal defects. This category of heart defects is also known as outflow tract defects and includes tetralogy of Fallot, interrupted aortic arch, ventricular septal defect and truncus arteriosus.
- In 69% of cases, defects of the palate (the roof of the mouth) also occur, especially velopharyngeal incompetence (air leakage through the passage between the back of the mouth and the nasal passages that allows air to escape through the nose during speech), submucosal cleft palate (a split in the soft part of the palate close to the back of the mouth), bifid uvula (a split in the small structure that dangles down at the back of the mouth and is attached to the rear of the soft palate), and cleft palate (a split in the roof of the mouth. A cleft can be in the hard palate, soft palate or both).
- Characteristic facial features often aid in making the diagnosis and include a prominent nose with a rounded tip, smaller than average eye openings, flattened cheek bone areas, a long face, a small chin and a small head.
- Learning difficulties of varying degrees are eventually evident in the majority (between 70% and 90%) of children with 22q11.2 deletion syndrome.
- In addition, the immune system (the system that protects against infectious disease) does not function normally in just over three quarters (77%) of cases, making these children prone to infection.
Other features that may occur less often in some people include:
- Hypocalcemia (low levels of calcium in the blood), which occurs in about half of people with a 22q11.2 deletion. Hypocalcemia may result in seizures.
- Thyroid function may be affected, with either an under active (20% of people) or over active thyroid (5% of people).
- Weakened function of, or unusual structure of the urinary tract (kidneys and bladder working together to remove waste from the body) may be present. These may include a structural urinary tract anomaly (something that is different than expected) in just under a third (31%) of people with the syndrome. In 10% to 11% of children, dysfunctional voiding, unilateral renal agenesis (a missing kidney) or multicystic dysplastic kidneys (kidneys with many cysts that may not function properly) are also present.
Short-Term Treatment and Outcomes
The number and type of associated features will determine the management for each person with 22q11.2 deletion syndrome. Often the first feature noted is a cleft palate (birth defect of the roof of the mouth), which can, along with other factors, complicate feeding. Other common features affecting the digestive tract include acid reflux (stomach acid coming up and irritating the esophagus), dysphagia (difficulty or discomfort swallowing), and constipation (hard stools that make bowel movements difficult). Approximately a third (36%) of children have considerable issues with feeding, some requiring feeding through a tube. A feeding consult may help to identify the best method to assure that enough food is being ingested to support the child's growth.
A heart murmur or cyanosis (dusky blue color around the lips and nails) may be evident if a heart defect is present, though not always. Depending upon the particular heart defect, surgery may be needed soon after birth. Often, though, the surgical repair happens later when the baby has had a chance to get a little bigger. Later in life, additional cardiac procedures may be needed, depending upon the type of heart defect that was originally present.
If the parathyroid glands are not producing enough parathyroid hormone, blood calcium levels may be very low, which may result in seizures. Checking thyroid function is also important to do in early life. Both conditions can be managed with hormone replacement therapy that supplements whichever hormone level is low.
Evaluation to determine the function of the immune system should be done as soon as possible. A complete blood cell count which tallies the type and number of blood cells that are present, and an immunoglobulin analysis are early tests to help identify any gaps in immune system function. If these tests are outside of normal limits, especially if the T cell count is very low or absent, an immunology consult should be arranged as soon as possible. In children with impaired immune systems, vaccinations with live vaccines are generally not recommended and infections should be treated aggressively. Immune system function, especially T cell levels, tends to improve with age in these children. However, children with 22q11.2 deletion syndrome tend to have lower resistance to infection, especially upper respiratory infections, even when all immunologic tests appear normal.
Developmental delay is often seen in children with 22q11.2 deletion syndrome, including a delay in language. As the child grows older, intellectual disability and learning differences are likely to become more obvious. Verbal IQ is often greater than performance IQ as the child grows. Early intervention services are often helpful in maximizing a child's developmental potential.
Long-Term Treatment and Outcomes
As the child grows, skeletal features such as scoliosis (curvature of the spine) and differences in the shape of the cervical spine may become apparent. Scoliosis develops in almost half (45%) of children with 22q11.2 deletion syndrome, though only a small minority of these children (6%) require corrective surgery.
Developmental delays in language and motor skills may become increasingly evident as a child approaches school age. If a significant intellectual disability is present, special educational services are important to assure that each child develops to his/her fullest potential.
Short stature can also be a part of the syndrome and is sometimes caused by growth hormone deficiency, but not always. Recurrent infections and additional cardiac surgery can impact school attendance.
Upon entry into later adolescence and young adulthood, psychological and psychiatric illness may develop. By adulthood, up to 50% to 60% of adults will have suffered from psychiatric illness, but many are treatable. Some 20% or more of young adults will develop schizophrenia or other psychotic disorder.
Implications for Children's Development
Children with 22q11.2 deletion syndrome will usually have developmental delays that include both motor and speech and language areas. Enrollment in Early Intervention services may help to maximize development. Otitis media (inflammation inside the ear) may also result in conductive hearing loss that may increase developmental delays in speech and language. In addition, once speech commences, children with 22q11.2 deletion syndrome often have a hypernasal quality to their speech (nasal sounding). Working with a speech pathologist may help to minimize this tendency.
In general, intelligence scores are shifted lower, with the average IQ in the low 70's. About 30% of children will have an IQ between 80 and 100, which is in the normal range. Memory and rote learning (memorization) is often a strength for these children and this may help them perform better in some school settings, but abstract reasoning (ability to analyze and solve a problem) is often more difficult.
As these children grow, they have a greater chance of developing emotional, behavioral and psychiatric conditions. Attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, depression, bipolar disorder, anxiety disorders and autistic spectrum disorder (ASD) have all been reported. In adolescence and adulthood, the chance for developing other mental health conditions increases. At least two studies have observed that schizophrenia has developed in some adults with 22q11.2. Young people with 22q11.2 deletion syndrome will often benefit from involvement with mental health professionals (psychologists and psychiatrists) at an early age who can identify symptoms of a mental health condition as early as possible and manage treatment as needed.
Although a diagnosis of 22q11.2 deletion syndrome presents many challenges for the physical and mental health of the child and his/her family, early diagnosis and consistent support by parents, educators and medical providers can improve and maximize the child's health, development and wellbeing across their life span.