What is DiGeorge Syndrome?
DiGeorge Syndrome (DGS) is a medical condition that occurs when certain body structures don’t develop correctly during embryonic growth. This syndrome, first explained by Dr. Angelo DiGeorge in 1965, includes immune deficiency, low levels of parathyroid hormone (hypoparathyroidism), and congenital heart disease.
This syndrome is part of a larger group known as 22q11 deletion syndromes, including Shprintzen-Goldberg syndrome, velocardiofacial syndrome, and others. Even though these syndromes all have the same genetic origin, they present differently, which has led to various naming and some confusion in diagnosis. Currently, the names of these syndromes are often used interchangeably.
Major characteristics of DGS encompass an under-developed or missing thymus gland, heart irregularities, low calcium levels, and an underactive parathyroid gland. Possibly the most alarming feature of this syndrome is the lack of thymic tissue, as the thymus is key in the development of T-lymphocytes, a type of white blood cell specialized in specific immune functions. The complete absence of the thymus is infrequent, occurring in less than 1% of DGS patients, but it correlates with severe combined immunodeficiency (SCID). Patients with DGS could have varying degrees of immune deficiency based on how developed the thymus gland is.
Other symptoms may include mild to moderate immune deficiency, various heart defects, and abnormalities of the palate, kidney, eyes, and digestive system. Concerns also include skeletal defects, mental health disorders, and developmental delays. Cognitive development can range from minor decline to more serious intellectual disability, varying from person to person. Owing to these differences, individual care, thorough assessment, and interdisciplinary treatment throughout the patient’s life are necessary.
What Causes DiGeorge Syndrome?
About 90% of cases of DiGeorge Syndrome (DGS) are linked to a missing piece in chromosome 22, specifically at a particular location known as 22q11.2. In most situations, this genetic change happens out of the blue, meaning the parents of children with DGS typically don’t have any genetic abnormalities.
Scientists have found over 90 different genes in this area of the chromosome, and some of them have been studied in mice. One gene that has been extensively studied is the T-box transcription factor 1 (TBX1). In mice, this gene is connected to severe problems in the growth of the heart, thymus, and parathyroid glands. It’s also linked to abnormalities in small nerve vessels, which might be the cause of the behavioral and developmental problems seen in DiGeorge Syndrome.
Risk Factors and Frequency for DiGeorge Syndrome
The 22q11.2 microdeletion syndrome is the most common of its kind, affecting about 0.1% of unborn babies. In live births, this syndrome is estimated to occur in 1 out of every 4,000 to 6,000 babies. This difference in occurrence between unborn and born babies can be due to several reasons. First, research might not have included enough number of cases. Second, this syndrome might lead to conditions that could be fatal before birth, which was evident in animal studies.
Actually, the 22q11.2 microdeletion syndrome might be more prevalent than what is reported in medical research. This can be attributed to various reasons. For instance, not everyone with this syndrome shows the usual face abnormalities and therefore, might not have undergone genetic testing. An example can be seen in African-American children who may not display these typical facial features. Another reason is that not everyone may have access to healthcare and specifically to genetic testing, which can help detect this syndrome. So, regardless of the severity of the facial irregularities, there might be individuals who were never diagnosed with this condition. This is why there is a need for more extensive research to better understand the spectrum of the 22q11.2 microdeletion syndrome in different population groups.
Signs and Symptoms of DiGeorge Syndrome
DiGeorge syndrome (DGS) is a condition that displays a broad range of severity and can be diagnosed at different stages in life, often during the prenatal or pediatric periods but also as late as adulthood. Early signs often include delays in motor development, such as taking longer to roll over, sit up, and hit other infant milestones. Delayed speech development and learning disabilities may also be indicators. Later in life, abnormal behavior or signs of learning disabilities might be the first clues to this condition.
When evaluating for DiGeorge syndrome, a detailed medical history may reveal the following:
- A family history of diagnosed or suspected DGS
- Abnormal genetic testing results in family members
- Delays in achieving developmental milestones
- Behavioral disturbance
- Symptoms like bluish skin during exercise (cyanosis) and frequent infections due to a weakened immune system
- Difficulties with speech
- Challenges feeding and slow weight gain
- Muscle spasms or seizures
Physical examinations can show specific features connected with DiGeorge syndrome:
- Heart or lung issues could manifest as heart murmurs, bluish skin (indicating lack of oxygen), swollen fingers or toes, and defects in the heart structures.
- Facial anomalies such as cleft palate, wide-set eyes, unusual ear shapes, drooping eyelids, a short ridge between the nose and mouth, and underdeveloped jaws.
- Frequent sinus or lung infections due to a weakened immune system
- Signs of low blood calcium, such as muscle twitching and spasms, due to underdeveloped parathyroid glands. A person might test positive for Chvostek’s or Trousseau’s signs, both of which indicate low calcium.
- Delayed development and unusual behaviour or signs of psychiatric disorders.
The exact symptoms and their severity can vary widely among individuals with DiGeorge syndrome.
Testing for DiGeorge Syndrome
A definitive diagnosis of DiGeorge Syndrome (DGS) is made when there is a tiny missing piece (microdeletion) on chromosome 22, at a specific location known as 22q11.2. Regular tests for genetic abnormalities, like trisomies, can’t detect these tiny missing pieces so special tests are used. These special tests include fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), single nucleotide polymorphism (SNP) array, comparative genomic hybridization (CGH) microarray, or quantitative polymerase chain reaction (qPCR). However, these tests can be expensive and not always available which can delay the diagnosis, mainly in areas with fewer resources.
People who are diagnosed with or suspected to have DGS need to undergo extensive testing, especially if there are severe heart or immune system-related issues. The tests might include things like an echocardiogram to check your heart, a complete blood count to check your blood cells, a check of T and B lymphocyte cells, a test to assess the T cell repertoire, measuring of immunoglobulin levels, testing the response to vaccines, measuring of serum ionized calcium and phosphorus levels, checking parathyroid hormone levels, a chest x-ray to look at your thymus, a renal ultrasound to check your kidneys and urinary system, serum creatinine levels, thyroid-stimulating hormone (TSH) levels, and testing for growth hormone deficiency.
DiGeorge Syndrome can vary widely in severity, which can make it hard to diagnose and evaluate. Cases with significant heart, thymus, and facial issues are easier to identify than those without severe features. Using advances in genome studies and facial recognition technology could help doctors diagnose and evaluate people with DiGeorge Syndrome more effectively.
Treatment Options for DiGeorge Syndrome
People with DiGeorge Syndrome (DGS) require specialized healthcare from a team of professionals. Most DGS patients have a minor weakened immune system, but their T cells — a type of immune cell — still function properly even though they produce fewer of these cells. It’s important to regularly visit an immunologist who has experience with primary immune deficiencies. If a newborn has complete DGS, needing to be managed with isolation, infusion of antibodies (intravenous IgG), antibiotics to prevent infections, and cell transplants from the thymus or blood stem cells.
Each DGS patient’s treatment plans, including immunizations, intravenous injections of antibodies, and antibiotics, should be based on their individual test results. Their response to vaccinations should be checked every six to twelve months to determine whether they need to be re-vaccinated. Although some controversy surrounds the use of live vaccines like MMR, oral polio, and rotavirus for these patients, it is generally considered safe for children over one year old who have certain levels of T cells. Note, however, that rotavirus vaccination can cause diarrhea in patients with very low T cell counts and should be avoided.
As part of treatment and management, DGS patients with heart abnormalities may require urgent evaluation by a pediatric heart surgeon. If blood transfusions are needed, the blood should be treated in certain ways to prevent complications. Patients with a cleft palate should see a specialist for surgical correction, which can improve their ability to eat and talk and reduce the chances of sinus and lung infections. Low calcium levels can be managed with supplements of calcium and vitamin D.
Autoimmune diseases, including types of arthritis, anemia, and thyroid diseases, are common in DGS patients. These patients should be regularly checked for symptoms of these diseases. An audiologic evaluation is beneficial if a DGS patient is having hearing problems. Speech therapy and early intervention services can help children who are having trouble with language or cognitive and behavioral development due to DGS or the conditions associated with it.
Mental health care may be necessary for DGS patients who have depression or psychosis. Genetic counselling could be considered if a person with DGS or their parents are planning to have more children. If a parent has the same genetic mutation as a child with DGS, there’s a 50% chance that another child will also have DGS.
For children with the most severe form of DiGeorge anomaly (cDGS), current treatment approaches include hematopoietic or thymus cell transplants. These children often die by the age of two due to severe infections because their bone marrow stem cells can’t develop into T cells. One survey found that the survival rate after this type of transplant was 33% from unrelated donors and 60% from sibling donors. Thymus transplantation, recently approved by the FDA and involves transplanting thymus tissue into the patient’s thigh muscles, brings about a 75% survival rate. However, surviving patients often face subsequent autoimmune conditions, like autoimmune hemolysis and thyroiditis.
What else can DiGeorge Syndrome be?
DiGeorge syndrome can present with various symptoms, but these symptoms may also be seen separately in otherwise healthy individuals. So, it can sometimes be confused with other conditions, which share some of the same characteristics.
Here are some conditions that have overlapping features with DiGeorge syndrome:
- Smith-Lemli-Opitz syndrome, which often includes extra fingers or toes (polydactyly) and a cleft palate.
- Oculo-auriculo vertebral (Goldenhar) syndrome, showing issues with the ears, heart, spine, and kidneys. This usually occurs randomly.
- Alagille syndrome, with spine abnormalities, heart issues, and eye problems similar to DiGeorge syndrome.
- VATER association, involving heart, spine, kidney, and limb abnormalities, which is usually diagnosed when no other cause can be found.
- CHARGE syndrome, which might show a combination of heart defects, different palate formation, blocked nasal passages, eye defects, kidney issues, growth problems, ear/hearing abnormalities, facial paralysis, developmental delays, and immunity issues.
To ensure a correct diagnosis for DiGeorge syndrome, a genetic consultation is extremely important. This, combined with a thorough examination of all the individual’s symptoms, helps make an accurate diagnosis.
What to expect with DiGeorge Syndrome
Less than 1% of patients with the 22q11.2 microdeletion have a very severe form of DiGeorge Syndrome (DGS), which unfortunately has a poor prognosis. Without a special type of transplant (thymic or hematopoietic cell), these patients typically do not survive beyond their first year of life. Even with a transplant, the outlook remains grim. In a particular study, only 36 out of 50 infants who received a thymic transplant for this severe type of DGS survived to their second year.
The outlook for patients with a less severe form of DGS, known as partial DGS, is not clearly defined as it varies based on the severity of health problems associated with the disease. While some do not survive infancy because of severe heart defects, many live into adulthood. It’s worth noting that DGS might be significantly underdiagnosed and many undiagnosed adults with DGS may live normal lives in the community, with only minor intellectual or social issues and unnoticeable birth defects. As genetic testing improves, we hope to increase our understanding of DGS in the future.
Possible Complications When Diagnosed with DiGeorge Syndrome
Patients with DGS, or DiGeorge Syndrome, often need surgeries to fix heart and face abnormalities. As with all surgeries, there are risks involved, such as bleeding, infection, and a longer stay in the hospital. These risks are particularly high for DGS patients with a severely weakened immune system.
Consistent check-ups are essential for patients with DGS to monitor any potential complications. These complications could include:
- Repeated severe infections
- Autoimmune diseases
- Certain types of blood cancer
Preventing DiGeorge Syndrome
Parents of children who have DiGeorge Syndrome (DGS) should be thoroughly educated about their child’s condition, its severity, and related issues. There are several key areas that should be part of this learning process:
Parents should learn to recognize the early signs and symptoms of infection in their child. Similarly, indicators of low calcium levels in the blood, known as hypocalcemia, should also be straightforward to them.
It is crucial for parents to understand how to administer medications safely. They should also be well-versed in potential surgical treatments and immune therapy options.
Understanding genetic counseling can also be beneficial for these parents. Communication difficulties are common in DGS, so parents should be ready to use speech therapy for feeding or language issues.
Parents should also be informed about the developmental milestones that their child should reach and be able to detect any warning signs of developmental delays. They should also be aware of the benefits of early intervention programs.
In addition, the signs and symptoms of psychiatric disorders should be easy to recognize for them, as these conditions can often coexist with DGS.
