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Velocardiofacial Syndrome

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Description: Velocardiofacial syndrome is a genetic disorder characterized by congenital heart defects, facial abnormalities, and learning difficulties due to a deletion on chromosome 22.
Type: Velocardiofacial syndrome, also known as 22q11.2 deletion syndrome, is a chromosomal disorder. It is typically inherited in an autosomal dominant manner.
Signs And Symptoms: The features of this syndrome vary widely, even among members of the same family, and affect many parts of the body. Characteristic signs and symptoms may include birth defects such as congenital heart disease, defects in the palate, most commonly related to neuromuscular problems with closure (velopharyngeal insufficiency), learning disabilities, mild differences in facial features, and recurrent infections. Infections are common in children due to problems with the immune system's T cell-mediated response that in some patients is due to an absent or hypoplastic thymus. DiGeorge syndrome may be first spotted when an affected newborn has heart defects or convulsions from hypocalcemia due to malfunctioning parathyroid glands and low levels of parathyroid hormone (parathormone).Affected individuals may also have other kinds of birth defects including kidney abnormalities and significant feeding difficulties as babies. Gastrointestinal issues are also very common in this patient population. Digestive motility issues may result in constipation. Disorders such as hypothyroidism and hypoparathyroidism or thrombocytopenia (low platelet levels), and psychiatric illnesses are common late-occurring features.Microdeletions in chromosomal region 22q11.2 are associated with a 20 to 30-fold increased risk of schizophrenia. Studies provide various rates of 22q11.2DS in schizophrenia, ranging from 0.5 to 2.0% and averaging about 1.0%, compared with the overall estimated 0.025% risk of the 22q11.2DS in the general population.Salient features can be summarized using the mnemonic CATCH-22 to describe 22q11.2DS, with the 22 signifying the chromosomal abnormality is found on the 22nd chromosome, as below:
Cardiac abnormality (commonly interrupted aortic arch, truncus arteriosus and tetralogy of Fallot)
Abnormal facies (Hypertelorism, short down slanting palpebral fissures, tubular nose with anteverted nostrils, short philtrum, carp mouth, mandibular hypoplasia, cleft palate)
Thymic aplasia or hypoplasia
Cleft palate
Hypocalcemia/hypoparathyroidism early in lifeIndividuals can have many possible features, ranging in number of associated features and from the mild to the very serious. Symptoms shown to be common include:

This syndrome is characterized by incomplete penetrance. Therefore, there is a marked variability in clinical expression between the different patients. This often makes early diagnosis difficult.
Prognosis: Velocardiofacial syndrome (VCFS), also known as DiGeorge syndrome or 22q11.2 deletion syndrome, has a variable prognosis depending on the severity and combination of symptoms experienced by the individual. Early intervention and consistent medical management can significantly improve quality of life. Common interventions may include cardiac surgery, speech therapy, educational support, and appropriate treatments for associated psychiatric and immunological conditions. Regular follow-ups with a multidisciplinary team of healthcare providers are essential for optimal outcomes.
Onset: Velocardiofacial syndrome typically has an onset at birth. The signs and symptoms can vary but are often noticeable in infancy or early childhood.
Prevalence: The prevalence of velocardiofacial syndrome, also known as 22q11.2 deletion syndrome, is estimated to be about 1 in 4,000 live births.
Epidemiology: DiGeorge syndrome is estimated to affect between one in 2000 and one in 4000 live births. This estimate is based on major birth defects and may be an underestimate, because some individuals with the deletion have few symptoms and may not have been formally diagnosed. It is one of the most common causes of intellectual disability due to a genetic deletion syndrome.The number of people affected has been expected to rise because of multiple reasons: (1) surgical and medical advances, an increasing number of people are surviving heart defects associated with the syndrome. These individuals are in turn having children. The chances of a person with DiGeorge syndrome having an affected child is 50% for each pregnancy; (2) Parents who have affected children, but who were unaware of their own genetic conditions, are now being diagnosed as genetic testing become available; (3) Molecular genetics techniques such as FISH (fluorescence in situ hybridization) have limitations and have not been able to detect all 22q11.2 deletions. Newer technologies have been able to detect these atypical deletions.
Intractability: Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is not inherently intractable. The condition has a wide range of symptoms that vary in severity among individuals. While there is no cure, many of its symptoms and associated health issues can be managed with appropriate medical care, therapies, and support. Treatment often involves a multidisciplinary approach, involving specialists such as cardiologists, immunologists, speech therapists, and educators, tailored to address the specific needs of the individual.
Disease Severity: Velocardiofacial syndrome, also known as 22q11.2 deletion syndrome or DiGeorge syndrome, varies in severity. The symptoms and their intensity can differ widely among affected individuals. Some may have mild manifestations that require little intervention, while others may experience severe issues, including congenital heart defects, immune system deficiencies, cleft palate, and developmental delays. The combination and severity of symptoms will dictate the overall impact on health and quality of life.
Healthcare Professionals: Disease Ontology ID - DOID:12583
Pathophysiology: Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, primarily results from a microdeletion on chromosome 22 at the q11.2 location. This deletion affects a small number of genes, leading to a wide spectrum of clinical manifestations. The pathophysiology involves disrupted development of the pharyngeal arches, which contribute to defects in the heart, face, and thymus. The gene TBX1 is considered a key player, and its loss is believed to cause many of the cardiovascular anomalies associated with the syndrome. Other affected genes may contribute to the broad array of symptoms, including immune deficiencies, palatal abnormalities, and developmental delays.
Carrier Status: Velocardiofacial syndrome, also known as 22q11.2 deletion syndrome, is not typically associated with a "carrier status" in the same way as some other genetic conditions. It results from the deletion of a small piece of chromosome 22. This deletion often occurs as a new mutation (de novo), meaning it commonly arises spontaneously rather than being inherited from a carrier parent. However, if a person with the syndrome has children, there is a 50% chance of passing the deletion on to each child.
Mechanism: Velocardiofacial syndrome (VCFS), also known as DiGeorge syndrome or 22q11.2 deletion syndrome, is primarily caused by a deletion of a small segment of chromosome 22 at the q11.2 region.

**Mechanism:**
The deletion of this chromosomal segment leads to the loss of several genes, which disrupts normal developmental processes. This results in the characteristic features of the syndrome, including congenital heart defects, facial dysmorphism, thymic hypoplasia, cleft palate, and learning disabilities.

**Molecular Mechanisms:**
The deletion often involves a hemizygous loss of around 30 to 40 genes in the 22q11.2 region. One of the most critical genes affected is TBX1. TBX1 encodes a transcription factor that is crucial for the development of the pharyngeal arches, which contribute to structures in the heart, face, and neck. Loss of TBX1 disrupts normal signaling pathways and transcriptional programs during embryogenesis, leading to the clinical manifestations of VCFS.

Other genes in the deleted region may also contribute to the phenotype, including:

- **COMT (Catechol-O-Methyltransferase)**: Associated with dopamine metabolism, potentially contributing to cognitive and psychiatric manifestations.
- **CRKL (CRK Like Proto-Oncogene, Adaptor Protein)**: Plays a role in signal transduction pathways that are important for cell growth and differentiation.

The combinatory effect of losing these genes disrupts multiple developmental pathways, ultimately leading to the diverse clinical features observed in individuals with VCFS.
Treatment: 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.Metirosine (methyltyrosine) is used as an off-label treatment for DiGeorge syndrome.
Compassionate Use Treatment: Velocardiofacial Syndrome (VCFS), also known as 22q11.2 deletion syndrome, generally requires a multidisciplinary approach to manage its wide array of symptoms. There isn't a specific compassionate use treatment universally recognized, as the management is tailored to the individual's symptoms.

Off-label or experimental treatments for VCFS may include:

1. **Psychiatric Medications**: Off-label use of antipsychotics, antidepressants, or mood stabilizers to manage psychiatric manifestations such as schizophrenia or anxiety.

2. **Growth Hormone Therapy**: Sometimes considered for short stature associated with VCFS, though it is not universally approved.

3. **Cardiac Interventions**: Some experimental approaches may be explored for congenital heart defects if conventional surgical or medical treatments are not effective.

4. **Immunoglobulin Therapy**: For those with immune deficiencies, immunoglobulin therapy might be considered.

It's essential for any off-label or experimental treatment to be closely monitored by a specialist familiar with VCFS.
Lifestyle Recommendations: Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, involves a variety of clinical features that require tailored lifestyle recommendations. These can vary depending on the individual's specific symptoms and needs. General lifestyle recommendations could include:

1. **Regular Medical Follow-ups**: Due to the potential for multiple organ involvement, regular check-ups with a variety of specialists (cardiologists, ENT specialists, immunologists, etc.) are crucial.

2. **Healthy Diet**: A well-balanced diet to support overall health, especially if the individual has feeding difficulties or gastrointestinal issues.

3. **Exercise**: Appropriate physical activity as recommended by healthcare providers. Physical and occupational therapy may be beneficial.

4. **Educational Support**: Customized learning plans and possibly special education services to address developmental delays and learning difficulties.

5. **Mental Health Care**: Regular psychological support to cope with the condition's emotional and social impacts, considering VCFS's association with psychiatric disorders.

6. **Speech Therapy**: Often necessary for speech and language delays.

7. **Social Skills Training**: Programs to enhance social interactions and functional skills.

8. **Avoidance of Substances**: Abstain from alcohol, tobacco, and recreational drugs to prevent exacerbating health issues.

These recommendations should be tailored to the individual's specific symptoms and developed in collaboration with a healthcare team familiar with VCFS.
Medication: Velocardiofacial syndrome, also known as 22q11.2 deletion syndrome or DiGeorge syndrome, often requires a multidisciplinary treatment approach. Medication management can vary depending on the specific symptoms and associated conditions present in the individual. Commonly prescribed medications may include:

1. **Antipsychotics or Mood Stabilizers:** For psychiatric and behavioral issues such as anxiety, depression, or psychosis.
2. **Stimulants or Non-Stimulant Medications:** For attention deficit hyperactivity disorder (ADHD).
3. **Anticonvulsants:** For seizure management if epilepsy is present.
4. **Calcium and Vitamin D Supplements:** For hypocalcemia (low calcium levels) resulting from parathyroid gland dysfunction.

A healthcare provider will tailor the medication regimen based on the individual's specific needs and symptoms. Regular monitoring and adjustments may be necessary.
Repurposable Drugs: Currently, there are no specific drugs approved solely for the treatment of velocardiofacial syndrome (VCFS). However, management typically involves addressing the various symptoms and complications associated with the condition. Repurposable drugs might include:

1. **Antipsychotics**: Medications like risperidone for managing psychiatric symptoms.
2. **Cardiac Medications**: Beta-blockers or ACE inhibitors if there are heart defects.
3. **Anticonvulsants**: Used for seizure management.
4. **Calcium Supplements**: For patients with hypocalcemia.

Clinical management often requires a multidisciplinary approach involving cardiologists, endocrinologists, neurologists, and psychiatrists.
Metabolites: For velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, specific metabolites typically associated with the syndrome are not well-documented in mainstream clinical research. However, individuals with VCFS may experience a variety of metabolic abnormalities due to associated endocrine disorders such as hypoparathyroidism, which can lead to alterations in calcium and phosphate metabolism. Additionally, they may experience disruptions in other metabolic pathways due to accompanying medical conditions. For precise metabolic profiles and impacts, clinical evaluations and individualized testing are necessary.
Nutraceuticals: Nutraceuticals for Velocardiofacial Syndrome (VCFS) do not have established efficacy. VCFS, also known as 22q11.2 deletion syndrome, primarily requires medical management tailored to individual symptoms, which may include congenital heart defects, immune deficiencies, and developmental delays. Nutritional supplements should only be used under medical supervision, considering the unique needs and underlying health conditions of each patient.
Peptides: Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is typically not directly associated with a specific peptide treatment. Management of VCFS usually involves addressing the array of symptoms and health issues it encompasses, such as heart defects, immune deficiencies, and developmental delays. While peptides might be involved in certain therapeutic research areas, they are not a standard treatment for this syndrome.