AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Robert Ardinger, Jr, MD, Pediatrics, Clinical Associate Professor, The Children's Mercy Hospital
Robert Ardinger, Jr, is a member of the following medical societies: American Academy of Pediatrics and American College of Cardiology
Coauthor(s):
Holly Ardinger, MD, Pediatrics, Clinical Associate Professor, The Children's Mercy Hospital
Editors: Jeffrey Towbin, MD, Associate Chair of Pediatric/Cardiology, Departments of Pediatrics, Molecular and Human Genetics, Cardiovascular, Professor, Baylor College of Medicine and Texas Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Ameeta Martin, MD, Associate Professor, Department of Pediatrics, Section of Pediatric Cardiology, University of Nebraska College of Medicine; Gilbert Herzberg, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College; Stuart Berger, MD, Professor of Pediatrics, Division of Cardiology, Medical College of Wisconsin; Chief of Pediatric Cardiology, Medical Director of Pediatric Heart Transplant Program, Medical Director of The Heart Center, Children's Hospital of Wisconsin
Author and Editor Disclosure
Synonyms and related keywords:
velocardiofacial syndrome, VCFS, DiGeorge sequence, Shprintzen syndrome, Shprintzen's syndrome, 22q11 deletion
Background
Velocardiofacial syndrome (VCFS) is a genetic condition characterized by structural or functional palatal abnormalities, cardiac defects, unique facial characteristics, hypernasal speech, hypotonia, developmental delay, and learning disabilities. Robert Shprintzen et al first described it in 1978. The cardiac defects are usually of the conotruncal type, which occur secondary to abnormal development of the outflow portion of the developing heart. Defects in this grouping that develop with VCFS include truncus arteriosus, tetralogy of Fallot, pulmonary atresia with ventricular septal defect, absent pulmonary valve syndrome, and interrupted aortic arch type B. Ventricular septal defects and aortic stenosis may also develop. D-transposition of the great arteries is rare.
Over 180 different clinical features are associated with VCFS, with no single anomaly present in every patient. Some abnormalities occur more commonly than others. About 10% of patients with VCFS have the DiGeorge sequence, which consists of at least 2 of the following features: conotruncal cardiac anomaly, hypoparathyroidism/hypocalcemia, and thymic aplasia/immune deficiency. As many as 15-20% of patients have Robin sequence, which includes small jaw, U-shaped cleft palate, and glossoptosis. Reports indicate that some patients with VCFS may be mistakenly categorized as having the CHARGE syndrome (ie, coloboma, heart defect, atresia choanae, retarded growth and development, and/or CNS anomalies, genital hypoplasia, and ear anomalies and/or deafness). VCFS is a specific syndrome that includes as part of its phenotypic spectrum the DiGeorge sequence, Robin sequence, and disorders associated with CHARGE syndrome.
Pathophysiology
This congenital disorder is caused by an abnormality of morphogenesis that, in part, affects the migration of the neural crest cells and the early development of branchial arches. At least 90% of patients have a deletion of the long arm of chromosome 22 (22q11) detectable with current cytogenetic and fluorescence in situ hybridization (FISH) techniques. In 90% of cases, the disorder occurs as the result of a new mutation, and in 10% the disorder is inherited from a parent in an autosomal dominant fashion.
Frequency
International
VCFS occurs in 1 per 4000 births worldwide, according to estimates. Among those with conotruncal heart defects, the incidence is 10-30%. Among those with cleft palate without an associated cleft lip, the frequency of VCFS is 8%.
Mortality/Morbidity
Truncus arteriosus, absent pulmonary valve syndrome and interrupted aortic arch type B are the most serious defects. Surgical correction, which must be performed in the infant, carries a higher risk. Unrecognized hypocalcemia can be associated with seizures. Psychiatric illness, such as schizophrenia or bipolar disorder, can develop in 10% of adults with this condition. Abnormal course of the internal carotid arteries and other blood vessels in the pharynx can create a significant surgical risk during pharyngoplasty for velopharyngeal incompetence.
Race
No racial predilection exists.
Sex
No sexual predilection exists.
Age
VCFS is present at birth but may not be recognized until childhood or later. A heart defect or overt cleft palate may be detected prenatally or at birth. A submucous cleft palate, velopharyngeal incompetence (VPI), or speech and developmental delay may not be recognized until the child is older than 1 year. Hypernasal speech is common. Learning disorders and psychiatric illness may become apparent between school age and adulthood.
History
- Cyanosis may be present if cardiac disease is coexistent (eg, truncus arteriosus, tetralogy of Fallot).
- Feeding difficulty and slow growth may occur due to congestive heart failure, palatal abnormality, or hypotonia.
- Nasal regurgitation of formula in infancy is common in patients later diagnosed with submucous cleft palate.
- Delayed speech development associated with poor articulation and hypernasality can be caused by velopharyngeal incompetence. Patients may be unresponsive to speech therapy.
- Recurrent otitis media associated with palatal abnormality can contribute to speech delay and hearing loss, which often require the placement of ventilating tubes.
- Developmental delay in infants with a learning disorder becomes apparent in childhood. ADHD occurs in 35-55% of persons with VCFS.
- Poor social interaction or behavioral difficulties are common. Psychiatric disorders (including obsessive-compulsive disorder and schizophrenia) are reported in at least 10% of patients.
- Seizures related to hypocalcemia generally occur in the first year of life. The hypocalcemia generally resolves spontaneously over time, although a small number of patients present with hypocalcemia in the teen years. Frequent upper respiratory infections are commonly reported.
- Short stature has been reported in approximately 30% of patients with VCFS.
Physical
- Cyanosis may be present if there is an obligate systemic-to-pulmonic (right-to-left) shunt
- A heart murmur is present in most patients with a cardiac defect.
- Craniofacial dysmorphism
- Often, this is observed as a round face in infancy with prominent parietal bones and a bulbous nasal tip.
- The face appears long and hypotonic with narrow palpebral fissures, puffy upper eyelids, a squared nasal root, and a narrow alar base with thin alae nasi.
- Facial asymmetry, microcephaly, and small, often unusually shaped, ears may be noted at any age.
- A palatal abnormality can manifest as an overt cleft palate affecting the hard or soft palate or as a submucous cleft palate that can be detected upon palpation of the hard palate. Even a normal-appearing palate can be associated with velopharyngeal incompetence.
- Hypernasal speech and poor articulation often are observed.
- Hypospadias or cryptorchidism may be present in males.
- Varying degrees of hypotonia are observed in patients and may be associated with delay of motor, speech, and feeding skills. The presence of developmental delays is independent from the presence of a hearing defect.
- Long and tapering fingers are a common sign of VCFS.
Causes
- Most patients with VCFS have a deletion of the long arm of chromosome 22. About 10% of patients inherit this deletion from a parent, and the rest have it as the result of a new mutation.
- Abnormal exchange between chromosome 22s during meiosis is the predominant mechanism for this deletion.
- Patients have a 50% chance of passing VCFS on to each offspring.
Interrupted Aortic Arch
Tetralogy of Fallot With Absent Pulmonary Valve
Tetralogy of Fallot With Absent Pulmonary Valve
Tetralogy of Fallot With Pulmonary Atresia
Transposition of the Great Arteries
Truncus Arteriosus
Other Problems to be Considered
DiGeorge sequence
Expressive speech delay
Isolated cleft palate
Isolated congenital heart disease
Robin sequence
Lab Studies
- Use high-resolution (650 band level and above) chromosome analysis to look for a chromosome region 22q11 deletion.
- Fluorescence in situ hybridization (FISH) for a chromosome region 22q11 deletion must be performed to rule out a submicroscopic deletion (see Image 1). In addition, both parents of a proband should undergo chromosome analysis and 22q11 FISH testing to determine if either is a carrier (frequency is 10%). This allows for accurate recurrence risk estimates.
- Check serum calcium in diagnosed newborns and in any patients with suspected VCFS at any age who have seizures.
- Perform immune studies (T-cell marker studies) as directed by a pediatric immunologist on all infants with this diagnosis and in older individuals who have a history of frequent infections.
Imaging Studies
- A chest radiograph can show evidence of a heart defect.
- An echocardiogram is needed to rule out a heart defect, even in the absence of a heart murmur.
- Renal ultrasonography is used to look for a structural anomaly.
- Brain MRI is used if a severe delay is present.
Other Tests
- An ECG can help determine the presence of a heart defect.
- To detect hearing loss, conduct audiology testing at the time of diagnosis and at least annually thereafter.
Procedures
- Cardiac catheterization is not necessary for most patients with VCFS but might be indicated to evaluate and treat specific cardiac lesions.
Medical Care
- Evaluation usually occurs in an outpatient setting. In newborns, diagnosis may be made in the hospital.
- If needed, use medical therapy to treat heart failure, hypocalcemia, immune deficiency, feeding problems, and inadequate growth.
Surgical Care
- Cardiac surgery (use irradiated blood products)
- Repair of cleft palate
- Pharyngeal flap surgery for velopharyngeal incompetence (VPI) and improvement in hypernasality (In planning the surgery, consider the fact that the internal carotid is commonly medially displaced and tortuous.)
- Ventilation of ear tubes
Consultations
- Pediatric cardiologist
- Cardiothoracic surgeon
- Plastic surgeon (cleft palate)
- Endocrinologist
- Otolaryngologist
- Ophthalmologist
- Pediatrician (developmental)
- Psychiatrist
- Medical geneticist
Diet
No special diet is required, except as indicated for cardiac disease, feeding problems, growth problems, or other abnormalities.
Activity
Usually no restrictions are needed, except as indicated for cardiac disease or other abnormalities.
Administer medications for specific abnormalities as indicated (see Other Problems to be Considered).
Further Inpatient Care
- Admit a newborn with cyanosis for heart defect workup. Newborns with or without associated heart defects may require a prolonged hospitalization to work on feeding.
Further Outpatient Care
- Perform workup in an outpatient setting for other associated problems as needed.
Transfer
- Newborns requiring heart surgery may need transfer to a tertiary center.
Complications
- Congestive heart failure
- Pulmonary hypertension
- Psychiatric disorders
Prognosis
- Those without serious heart defects can expect a normal lifespan.
Patient Education
- Genetic counseling of the patient and family emphasizes that the velocardiofacial syndrome is dominant, that children of the patient have a 50% risk of being affected and that their children can be affected more or less severely than the parent.
- Prenatal diagnosis is available to detect the chromosome region 22q11 deletion.
- For excellent patient education resources, visit eMedicine's Heart Center. Also, see eMedicine's patient education article Tetralogy of Fallot.
Medical/Legal Pitfalls
- Failure to recognize the condition
- Failure to perform chromosome testing
- Failure to test the chromosomes of the parents or children of the affected person
- Failure to give correct genetic counseling
- Failure to use irradiated blood
Special Concerns
- Consider VCFS in any fetus diagnosed with conotruncal coronary heart disease on prenatal ultrasound.
- To make a prenatal diagnosis, perform amniocentesis for cytogenetic and FISH testing.
- Considerable variability in manifestations is noted among affected family members.
| Media file 1:
Chromosomal fluorescence in situ hybridization (FISH) demonstrating the deletion of one chromosomal region 22q11 segment. |
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| Media file 2:
Karyotype of a patient with a deletion of chromosome region 22q11. Complete karyotype is shown along with an enlargement of an image of chromosome 22 demonstrating the deletion. |
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Velocardiofacial Syndrome excerpt Article Last Updated: Apr 25, 2006
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