What is Velocardiofacial Syndrome?
DiGeorge Syndrome, also known as velocardiofacial syndrome or Chromosome 22q11.2 syndrome, was first identified in the 1960s by Dr. Angelo Di George. This condition is the most common type of genetic disorder in humans where a small part of the genetic material is missing, specifically a 3 Mb deletion of LCR22A-D.
This syndrome can cause a variety of health problems and affect everyone differently. Some people may show only a few symptoms while others may experience severe and even life-threatening complications. Common symptoms include immune system problems, repeated infections, low calcium levels which could cause seizures, brain and neurological issues, mental health problems, short height, unusually small or large head, developmental delays, congenital heart issues, urinary tract and reproductive issues, along with abnormalities in the roof of the mouth.
Furthermore, more than 90% of people with this syndrome typically have specific facial features. These features can include a long, narrow face, a tube-like nose, thin openings between the eyelids, and a small mouth.
What Causes Velocardiofacial Syndrome?
Velocardial facial syndrome, a genetic condition, is caused when a tiny chunk of DNA goes missing on one copy of a person’s 22nd chromosome (referred to as 22q11.2). Most of the time, this deletion happens randomly. However, as people with the syndrome live into adulthood and have children, there is a 50% likelihood that their babies will also inherit the disorder. The deletion can occur at different points on the chromosome, resulting in variable symptoms based on where and what DNA is lost. The deletions are grouped into three categories: near the beginning (called proximal), in the middle (central), and at the end (distal).
This broken piece of chromosome generally occurs during the formation of eggs or sperm (by a process called meiotic exchange). Specific areas of the chromosome, which contain lower amount of repeated DNA sequences, are particularly prone to getting lost during this process. About 30 to 40 genes can be lost in this way. Most people with velocardial facial syndrome have 3 million base pairs (the building blocks of DNA) missing.
When the 22q11.2 region is absent, specific cells required for the formation of certain body structures, known as neural crest cells, do not migrate correctly during early development. This affects the creation of the third and fourth pharyngeal pouches, which are structures in the developing embryo that eventually form other body parts. Because of this, abnormalities in the thymus and parathyroid glands, as well as certain heart defects, occur. This can lead to problems with the immune system and low calcium levels. A specific gene named T-box transcription factor (TBX1), is thought to have a role in some of these migration abnormalities.
Risk Factors and Frequency for Velocardiofacial Syndrome
Velocardial facial syndrome, a condition mostly resulting from new spontaneous genetic defects that can then be passed down within a family, occurs in roughly 1 to 2 out of every 4000 babies born. This condition is more likely to be observed in cases involving heart deformities. It affects both boys and girls equally and is not tied to any specific ethnic group.
People with this syndrome usually have normal fertility levels, but there is a 50% likelihood of their children inheriting the condition.
Signs and Symptoms of Velocardiofacial Syndrome
Velocardial facial syndrome is a genetic disorder that could surface in newborn infants through serious birth defects like certain heart anomalies, an underdeveloped thymus gland, or throat and mouth abnormalities. This is especially likely if the baby also shows signs of low calcium levels in their blood. Some infants are diagnosed when they are screened for a severe type of immune deficiency.
In older children and adults, psychiatric problems can also suggest the presence of this syndrome. These can include learning difficulties, attention deficit disorder, or even schizophrenia and schizoaffective disorder, which are seen in up to 25% of patients.
Usually, the four signs most frequently seen are learning delays, heart abnormalities, issues with the roof of the mouth, and a weak immune system.
People with velocardial facial syndrome may exhibit some observant characteristics, both physically and behaviourally:
- Distinctive facial features such as long narrow face, tubular nose with a bulbous tip, narrow eyelid openings, small mouth, and ears
- Problems with learning, especially in maths
- A nasal speaking quality
- Low calcium levels and underactive parathyroid glands
- Unusually low or high thyroid activity
- Mental health issues, including schizophrenia, depression, autism, attention deficit, obsessive-compulsive disorder
- Frequent seizures
- Heart malformations
- Curvature of the spine
- Problems with kidneys and urinary-genital system
- A condition where the eyes do not align correctly (strabismus)
- Frequent infections
- Obesity
Testing for Velocardiofacial Syndrome
Multiplex ligation-dependent probe amplification (MLPA), a technique to detect genetic changes, and single nucleotide polymorphism arrays (SNP), a method used to study genetic variations, are commonly used to detect tiny deletions on chromosome 22q11, a gene associated with velocardial facial syndrome. Another technique, fluorescence in-situ hybridization, can also be used to achieve this.
Pre-natal ultrasound can spot physical features, like an interrupted aortic arch, (a rare heart defect) that may suggest a baby might have velocardial facial syndrome. A study has suggested that if too much amniotic fluid (polyhydramnios) is found together with another minor unusual finding, genetic testing should be performed.
A common health issue for those with this syndrome is hypocalcemia, where there’s low calcium in the blood. This requires close monitoring.
Patients with this condition can also have thrombocytopenia with increased platelet size, a condition where there are fewer platelets than normal but they are larger in size. This happens when a specific gene associated with platelet function, GPIBB gene, is deleted and results in decreased function of the protein GPIb-IX-V on the blood platelets surface. As a result, this can often increase the patient’s likelihood for bleeding and frequent nosebleeds.
As patients with velocardial facial syndrome get older, they can develop hypothyroidism (an underactive thyroid) and hypoparathyroidism (when the body produces too little parathyroid hormone).
Treatment Options for Velocardiofacial Syndrome
Velocardiofacial syndrome (VCFS) is a genetic condition that impacts several features in a person’s body. VCFS often affects a person’s overall growth and development, and it is commonly associated with four significant features: developmental delays, heart abnormalities, unique facial features, and a weakened immune system. People with VCFS will likely require specialized medical care, and their treatment should be managed by a group of various medical specialists, focusing on their individual needs and age.
The heart issues that are most often linked with VCFS include defects such as tetralogy of Fallot (a combination of four heart defects that are present at birth), pulmonary atresia (a malformation of the pulmonary valve), truncus arteriosus (one large vessel instead of two separate vessels leading from the heart), an interrupted aortic arch (a gap in the aorta), and a ventricular septal defect (a hole in the heart wall). These heart defects can significantly affect a person’s health and lifespan, so it is recommended they receive treatment or monitoring from an experienced pediatric heart surgeon as early as possible.
With VCFS, someone may experience palatal defects, which refers to problems with the roof of the mouth. These defects can lead to feeding difficulties, especially for babies, because weak muscles in the upper throat area may interfere with swallowing. Sometimes, tube feeding—either through the nose or directly into the stomach—may be necessary to ensure proper nutrition. However, many people with VCFS can manage these difficulties with feeding thickeners and medications that control acid reflux. Breastfeeding may be challenging due to these abnormalities, so it’s important to discuss feeding options and plan care appropriately with parents of newborns with this condition.
People with VCFS may also have trouble maintaining proper calcium levels in their body. For these individuals, supplementing with calcium and vitamin D can help, but it’s also essential to monitor their levels carefully to prevent too much calcium, which can also be harmful.
As someone ages with VCFS, their medical needs will likely change. It’s important for parents to learn about this condition early so they can anticipate and address these changes. Additionally, using specialized growth charts for tracking development can provide valuable insights into the patient’s health and progress.
What else can Velocardiofacial Syndrome be?
Thymic aplasia and congenital hypoparathyroidism can occur in certain conditions. These include:
- CHARGE syndrome
- Chromosome anomalies on 4q21.3, 10p13-14, 11q23-ter
- Exposure to maternal diabetes or retinoic acid
Other conditions to keep in mind are Smith-Lemli-Opitz syndrome, Kabuki syndrome, and Goldenhar syndrome.
It’s crucial to remember that velocardiofacial syndrome can present in many ways. Hence, if a patient shows up with congenital anomalies, learning difficulties, and immune deficiencies, it may be a potential diagnosis.
What to expect with Velocardiofacial Syndrome
Complications from birth heart defects may lead to death in children (fewer than 4%), but due to advancements in understanding how to fix these defects, many patients are able to live into adulthood. Up until now, there’s no specific expected lifespan defined for these patients.
Possible Complications When Diagnosed with Velocardiofacial Syndrome
People with a condition known as velocardial facial syndrome often have heart problems that need to be fixed with surgery. However, these medical procedures, especially in newborn babies, can sometimes have complications. Before the procedure takes place, it is essential for doctors to discuss these risks with the parents.
In addition, about 10% of patients with velocardial facial syndrome also suffer from autoimmune diseases, possibly related to a weak immune system caused by an underdeveloped thymus gland. These patients might also have a higher tendency to develop allergies.
Prominent health issues related to this syndrome include idiopathic thrombocytopenia (a disorder that can lead to easy or excessive bruising and bleeding) and autoimmune hemolytic anemia (a breakdown of red blood cells). Both of these conditions are seen more frequently in patients with velocardial facial syndrome.
Other risks include blood cancers associated with a weak immune system. Recent studies also tie a specific type of tumor – the atypical teratoid/rhabdoid tumor linked to the SMARCB1 gene variant – with this syndrome.
Depending on how severely their immune system is impaired, these patients can be more prone to viral infections, especially during childhood. These infections may last longer and often have bacterial infections layered on top of them. It’s crucial that these patients are closely watched and given early treatment when necessary.
Concerns due to velocardial facial syndrome:
- Heart anomalies needing surgical repair
- Possibility of post-surgical complications
- Increased incidence of autoimmune diseases
- Possibility of allergies
- High frequency of idiopathic thrombocytopenia and autoimmune hemolytic anemia
- Increased risk of blood cancers
- Association with atypical teratoid/rhabdoid tumors due to SMARCB1 variant
- Higher risk of prolonged viral infections, combined with bacterial infections
- Need for close monitoring and early treatment
Preventing Velocardiofacial Syndrome
Children with velocardiofacial syndrome, a condition that affects many parts of the body, often have learning difficulties. Early help and support can be beneficial for these children. Parents should be well-informed about the regular growth and development milestones to observe in their child, as well as any signs of problems. This information will help them ensure their child gets help when it’s needed.
As they grow into teens and adults, individuals with this syndrome may show signs of mental health issues that are common with this condition, such as schizophrenia, depression, and attention deficit disorder. It’s important to have these potential issues discussed beforehand to prepare and deal with them effectively, if they arise.
There is no known link between environment, age, and the cause of velocardiofacial syndrome which is due to the missing part in chromosome 22 (chromosome 22q11).