22q11.2 deletion syndrome
Other Names: Chromosome 22q11.2 deletion syndrome; Velocardiofacial syndrome; VCFS; DiGeorge syndrome; Shprintzen syndrome; Sedlackova syndrome; CATCH22; Autosomal dominant Opitz G/BBB syndrome; Conotruncal anomaly face syndrome; Cayler cardiofacial syndrome
22q11.2 deletion syndrome is a disorder that involves many different areas of the body and can vary greatly in severity among people with the condition. 22q11.2 deletion syndrome (which is also known by several other names, listed above) 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.
22q11.2 deletion syndrome affects an estimated 1 in 4,000 people. However, the condition may actually be more common than this estimate because doctors and researchers suspect it is underdiagnosed due to its variable features. The condition may not be identified in people with mild signs and symptoms, or it may be mistaken for other disorders with overlapping features.
Most people with 22q11.2 deletion syndrome are missing a sequence of about 3 million DNA building blocks (base pairs) on one copy of chromosome 22 in each cell. This region contains 30 to 40 genes, many of which have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region. This condition is described as a contiguous gene deletion syndrome because it results from the loss of many genes that are close together.
Researchers are working to identify all of the genes that contribute to the features of 22q11.2 deletion syndrome. They have determined that the loss of a particular gene on chromosome 22, TBX1, is probably responsible for many of the syndrome's characteristic signs (such as heart defects, a cleft palate, distinctive facial features, hearing loss, and low calcium levels). Some studies suggest that a deletion of this gene may contribute to behavioral problems as well. The loss of another gene, COMT, in the same region of chromosome 22 may also help explain the increased risk of behavioral problems and mental illness. The loss of additional genes in the deleted region likely contributes to the varied features of 22q11.2 deletion syndrome.
The inheritance of 22q11.2 deletion syndrome is considered autosomal dominant because a deletion in one copy of chromosome 22 in each cell is sufficient to cause the condition. Most cases of 22q11.2 deletion syndrome are not inherited, however. The deletion occurs most often as a random event during the formation of reproductive cells (eggs or sperm) or in early fetal development. Affected people typically have no history of the disorder in their family, though they can pass the condition to their children. In about 10 percent of cases, a person with this condition inherits the deletion in chromosome 22 from a parent. In inherited cases, other family members may be affected as well.
Signs and symptoms
Signs and symptoms may include: cleft palate, heart defects, recurrent infections, unique facial characteristics, feeding problems, kidney abnormalities, hypoparathyroidism, thrombocytopenia, scoliosis, hearing loss, developmental delay, and learning disabilities. People with this condition are also more likely to develop certain autoimmune disorders and personality disorders.
The signs and symptoms of 22q11.2 deletion syndrome vary greatly from person to person, even among affected people in the same family. The most common symptoms include:
- Heart defects (74% of individuals)
- Abnormalities with the development of the palate (69% of individuals)
- Characteristic facial features (elongated face, almond-shaped eyes, wide nose, and small ears)
- Learning difficulties (70-90% of individuals)
- Immune system problems (77% of individuals)
Additional symptoms may include:
- Low levels of calcium (50% of individuals)
- Significant feeding problems
- Kidney anomalies (31% of individuals)
- Hearing loss
- Issues with the development of the larynx, trachea, and esophagus (laryngotracheoesophageal anomalies)
- Growth hormone deficiency
- Autoimmune disorders (thrombocytopenia, juvenile rheumatoid arthritis, overactive thyroid)
- Skeletal abnormalities (extra fingers, toes, or ribs, wedge-shaped spinal bones, craniosynostosis)
- Psychiatric illness
- Eye abnormalities (ptosis, coloboma, cataract, and strabismus)
- Central nervous system abnormalities
Developmental delay, intellectual disability, and learning differences are also common in individuals with 22q11.2 deletion syndrome. Individuals may also have an autism spectrum disorders. Psychiatric illness, attention deficit disorder, anxiety, repetitive behaviors, and difficulty with social interactions are also common.
The diagnosis of 22q11.2DS is established in a proband by identification of a heterozygous deletion at chromosome 22q11.2 . The majority of individuals (~85%) with 22q11.2DS have a heterozygous 2.54-Mb deletion, as described based on chromosomal microarray (CMA) designs, at the approximate position of g. 18,912,231-21,465,672 in the reference genome (NCBI Build GRCh37/ hg19) extending from flanking low copy number repeats (LCRs) A-D and including TBX1 . Note: Historically, the recurrent deletion has been described as a 3-Mb deletion.
CMA using oligonucleotide or SNP arrays can detect the recurrent deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 22q11.2 region.
Targeted deletion analysis. FISH analysis, quantitative PCR(qPCR), multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods may be used to test relatives of a proband known to have the 22q11.2 recurrent deletion.
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. 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.
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.
NIH genetic and rare disease info
22q11.2 deletion syndrome is a rare disease.