Velocardiofacial Syndrome
Velocardiofacial Syndrome
Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome or DiGeorge syndrome, is a genetic disorder characterized by a wide range of developmental abnormalities affecting multiple body systems. It is caused by a microdeletion on chromosome 22q11.2.
Key Points:
- Incidence: Approximately 1 in 4,000 live births, making it one of the most common microdeletion syndromes
- Inheritance: Autosomal dominant, but 90% of cases are due to de novo mutations
- Genetic basis: Deletion of 30-40 genes in the 22q11.2 region, with TBX1 gene being a major contributor to the phenotype
- Wide phenotypic variability, even within families
- Also known as CATCH22 syndrome (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, 22q11 deletion)
Clinical Features
The clinical presentation of VCFS is highly variable, but typically includes:
Craniofacial Features:
- Long face with malar flattening
- Hooded eyelids
- Broad nasal bridge and bulbous nasal tip
- Small mouth and micrognathia
- Ear abnormalities (low-set, overfolded helices)
- Cleft palate or submucous cleft (in about 70% of cases)
- Velopharyngeal insufficiency
Cardiovascular Abnormalities (present in 75% of cases):
- Tetralogy of Fallot
- Interrupted aortic arch
- Ventricular septal defects
- Truncus arteriosus
- Right-sided aortic arch
Immunological Features:
- Thymic hypoplasia or aplasia
- T-cell deficiency (variable severity)
- Increased susceptibility to infections
Endocrine Abnormalities:
- Hypoparathyroidism leading to hypocalcemia
- Thyroid dysfunction (hypo- or hyperthyroidism)
- Growth hormone deficiency
Neurological and Psychiatric Features:
- Developmental delays
- Intellectual disability (usually mild to moderate)
- Speech and language disorders
- Behavioral problems (ADHD, anxiety)
- Increased risk of psychiatric disorders (schizophrenia, bipolar disorder)
Other Features:
- Feeding difficulties in infancy
- Gastrointestinal issues (constipation, GERD)
- Renal anomalies
- Skeletal abnormalities
- Hearing loss
Diagnosis
Diagnosis of VCFS involves a combination of clinical features and genetic testing:
Clinical Diagnosis:
- Based on characteristic facial features, cardiac defects, and other associated anomalies
- High index of suspicion in patients with:
- Conotruncal cardiac anomalies
- Cleft palate
- Hypocalcemia in the neonatal period
- Characteristic facial features
Genetic Testing:
- Fluorescence in situ hybridization (FISH): Traditional method for detecting 22q11.2 deletion
- Microarray-based comparative genomic hybridization (aCGH): Provides more detailed information about the deletion size
- Multiplex ligation-dependent probe amplification (MLPA): Alternative method for detecting the deletion
- Next-generation sequencing: Can detect smaller deletions or point mutations in the TBX1 gene
Additional Investigations:
- Echocardiography: To evaluate cardiac structure and function
- Immune function tests: T-cell counts, immunoglobulin levels
- Calcium and parathyroid hormone levels
- Developmental and cognitive assessments
- Speech and language evaluation
- Renal ultrasound
- Audiological assessment
Differential Diagnosis:
- Other chromosomal disorders (e.g., Noonan syndrome, Williams syndrome)
- CHARGE syndrome
- Isolated congenital heart defects
- Isolated cleft palate
Management
Management of VCFS requires a multidisciplinary approach and is tailored to the individual's specific needs:
Cardiovascular Management:
- Surgical repair of congenital heart defects
- Ongoing cardiac monitoring
Immunological Management:
- Immunological evaluation and monitoring
- Prophylactic antibiotics if indicated
- Avoidance of live vaccines in cases of severe immunodeficiency
- Thymus transplantation in rare cases of severe immunodeficiency
Endocrine Management:
- Treatment of hypocalcemia (calcium and vitamin D supplementation)
- Management of thyroid dysfunction
- Growth hormone therapy if deficient
Speech and Feeding:
- Speech and language therapy
- Surgical correction of cleft palate and velopharyngeal insufficiency
- Feeding therapy and support
Developmental and Psychiatric Support:
- Early intervention programs
- Special education services
- Occupational and physical therapy
- Behavioral therapy and psychiatric management as needed
Other Interventions:
- Renal monitoring and management of renal anomalies
- Hearing aids or cochlear implants if indicated
- Orthodontic and dental care
- Regular ophthalmological examinations
Family Support:
- Genetic counseling
- Psychosocial support for patients and families
- Connection with support groups
Prognosis
The prognosis for individuals with VCFS is highly variable and depends on the severity of the associated features:
- Life expectancy:
- Normal in most cases with appropriate management
- May be reduced in cases with severe cardiac or immunological complications
- Developmental outcomes:
- Most individuals have mild to moderate intellectual disability
- Some achieve normal cognitive function
- Speech and language difficulties often persist but can improve with therapy
- Psychiatric outcomes:
- Increased risk of psychiatric disorders, particularly in adolescence and adulthood
- Early intervention and support can improve outcomes
- Long-term medical care:
- Ongoing monitoring for cardiac, immunological, and endocrine issues
- Regular follow-up with a multidisciplinary team
- Quality of life:
- Can be good with appropriate support and management
- Many individuals lead independent lives as adults
Early diagnosis, comprehensive management, and ongoing support are crucial for optimizing outcomes in individuals with VCFS.
