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22q11.2 deletion syndrome (DiGeorge)
This syndrome can affect various parts of the body, leading to a wide range of health challenges including heart defects, immune system problems, and developmental delays. It typically presents in infancy or early childhood and affects individuals from birth.
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Overview
22q11.2 deletion syndrome, often referred to as DiGeorge syndrome, is a genetic condition caused by the absence of a small section of genetic material on chromosome 22. This specific missing piece of the chromosome is known as a microdeletion. It is one of the most common microdeletion syndromes, affecting approximately 1 in 4,000 live births [PMID:24765126]. The features of the syndrome can vary considerably among affected individuals, even within the same family.
The condition can impact many different body systems, leading to a spectrum of health issues. These may include heart defects, problems with the immune system, distinctive facial features, difficulties with feeding, and developmental delays. The range and severity of these characteristics mean that managing the syndrome often requires a multidisciplinary approach involving several different medical specialists.
Symptoms & clinical features
The symptoms of 22q11.2 deletion syndrome are highly variable, meaning that no two individuals will experience the condition in exactly the same way. Common features often include congenital heart defects, which can range from mild to severe, and are sometimes detected shortly after birth [PMID:19426210]. Issues with the immune system are also frequent, typically due to problems with the thymus gland, an organ crucial for the development of certain immune cells. This can lead to increased susceptibility to infections.
Other clinical presentations may include difficulties with feeding and slow weight gain in infants, often linked to problems with muscle control in the mouth and throat. Distinctive facial features, such as small ears, a prominent nose, and a long face, can sometimes be observed. Developmental delays are also common, affecting speech, motor skills, and cognitive development. Some individuals may experience learning difficulties or behavioural challenges. In some cases, issues with calcium regulation, leading to low calcium levels (hypocalcaemia), may also be present, potentially causing seizures.
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Affected organs
22q11.2 deletion syndrome can affect a number of key organs and body systems. The heart is frequently involved, with many individuals born with structural heart defects. The immune system is also commonly affected, primarily due to an underdeveloped or absent thymus gland. This gland is essential for the maturation of T-cells, a vital component of the body's immune response.
The parathyroid glands, small glands located near the thyroid in the neck, can also be affected. These glands regulate calcium levels in the body, and their dysfunction can lead to hypocalcaemia. The palate, the roof of the mouth, may also be affected, sometimes resulting in a cleft palate or problems with speech. The brain and nervous system can be impacted, leading to developmental delays, learning difficulties, and an increased risk of certain psychiatric conditions in some individuals.
Risks & severity
The severity of 22q11.2 deletion syndrome varies greatly, from mild symptoms that may go undiagnosed for years to severe, life-threatening complications requiring immediate medical intervention. For instance, critical heart defects and profound immune deficiencies can pose significant risks in infancy. The lifetime risks associated with the syndrome are broad and depend on the specific combination of affected systems.
Developmental and learning difficulties are common, and individuals may require ongoing educational and therapeutic support throughout their lives. There is also an increased risk of psychiatric conditions, such as schizophrenia, anxiety disorders, and autism spectrum disorder, particularly in adolescence and adulthood. The age of onset for various symptoms can also differ; while heart defects and immune issues are often apparent in infancy, some developmental and behavioural challenges may become more noticeable as a child grows.
Genetic causes
22q11.2 deletion syndrome is caused by the absence of a small segment of genetic material on the long arm (q) of chromosome 22, at a specific location designated 11.2. This microdeletion typically spans approximately 1.5 to 3 million base pairs and includes about 30-40 genes [PMID:24765126]. The loss of these genes disrupts normal development and function of several body systems.
One of the key genes within this deleted region is TBX1. This gene provides instructions for making a protein, T-box transcription factor 1, which plays a crucial role in the formation of several tissues and organs during embryonic development. Research suggests that a reduction in the amount of TBX1 protein, due to the deletion of one copy of the gene, is a major contributor to many of the characteristic features of 22q11.2 deletion syndrome, especially heart defects and problems with the thymus and parathyroid glands [PMID:19426210]. The other genes in the deleted region also contribute to the varied symptoms observed in individuals with the syndrome.
- TBX1 T-box transcription factor 1
Inheritance pattern
22q11.2 deletion syndrome follows an autosomal dominant inheritance pattern. This means that a person only needs one copy of the altered gene (or in this case, one copy of the chromosome with the deletion) in each cell to develop the condition. In most cases, the deletion occurs spontaneously (de novo) during the formation of reproductive cells or early embryonic development, meaning neither parent carries the deletion.
However, in approximately 10% of cases, the deletion is inherited from an affected parent who also has the syndrome, though they may have milder symptoms. If a parent has 22q11.2 deletion syndrome, there is a 50% chance with each pregnancy that their child will also inherit the deletion. Genetic counselling is important for families to understand these inheritance risks and discuss family planning options.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of 22q11.2 deletion syndrome is primarily confirmed through genetic testing. Clinical suspicion often arises from the presence of characteristic features such as heart defects, immune problems, or developmental delay. Once suspected, a specific type of genetic test called fluorescence in situ hybridisation (FISH) or a chromosomal microarray analysis (CMA) can identify the microdeletion on chromosome 22. CMA is often preferred as it can detect smaller deletions that FISH might miss and can also identify other genetic changes.
Referral for genetic testing is typically made by a paediatrician or other specialist clinician who suspects the condition. In the UK, these tests fall under the NHS Genomic Medicine Service and are accessed via specific R-codes, such as R29 for microarray or R102 for 22q11.2 deletion testing. Clinical geneticists and genetic counsellors play a vital role in coordinating testing, interpreting results, and providing information and support to families.
Management & lifestyle
Management of 22q11.2 deletion syndrome is highly individualised, focusing on addressing the specific health concerns of each person. Due to the wide range of potential issues, a multidisciplinary team of healthcare professionals is typically involved. This may include cardiologists for heart defects, immunologists for immune system issues, endocrinologists for calcium problems, and speech and language therapists or physiotherapists for developmental delays.
Regular monitoring is crucial. For example, individuals with immune deficiencies may require preventative measures against infections, and calcium levels may need to be regularly checked and managed with supplements if necessary. Early intervention programmes, including educational support and various therapies, can significantly benefit development. In the UK, individuals with 22q11.2 deletion syndrome are managed within the NHS framework, often coordinated through specialist clinics, ensuring access to appropriate surveillance and interventions.
UK care pathway
In the UK, individuals suspected of having 22q11.2 deletion syndrome are typically referred to the NHS Genomic Medicine Service for diagnostic testing and ongoing care. This pathway involves specialist clinicians, such as paediatricians or clinical geneticists, who can request appropriate genetic tests under relevant R-codes (e.g., R29 or R102 for specific microdeletion analyses). Following diagnosis, patients are often managed within a multidisciplinary team approach. Genetic counsellors are integral to this pathway, providing essential information, support, and guidance to patients and their families regarding the condition, its inheritance, and available resources.
Frequently asked questions
What is the likelihood that my child will inherit 22q11.2 deletion syndrome from me?
If you have 22q11.2 deletion syndrome, there is a 50% chance with each pregnancy that your child will also inherit the deletion. Genetic counselling can provide personalised risk assessments and discuss family planning options.
Can 22q11.2 deletion syndrome be diagnosed before birth?
Yes, 22q11.2 deletion syndrome can be diagnosed prenatally through genetic testing, typically using chorionic villus sampling (CVS) or amniocentesis if specific concerns arise during pregnancy or if there's a known family history of the condition.
How does 22q11.2 deletion syndrome affect the immune system?
The syndrome often affects the thymus gland, which is crucial for developing certain immune cells called T-cells. An underdeveloped thymus can lead to a weaker immune system, making individuals more susceptible to infections.
Will a person with 22q11.2 deletion syndrome always have learning difficulties?
Learning difficulties are common in individuals with 22q11.2 deletion syndrome, but the severity varies widely. Some individuals may have mild difficulties, while others may experience more significant challenges, often benefiting from early intervention and specialised educational support.
Are there any specific treatments for 22q11.2 deletion syndrome?
There isn't a single 'cure' for the deletion itself, but treatments focus on managing the specific symptoms. This can include surgery for heart defects, calcium supplements for low calcium levels, and various therapies for developmental and speech delays, all tailored to the individual's needs.