Background
Velocardiofacial syndrome (VCFS) is a genetic condition characterized by abnormal pharyngeal arch development that results in defective development of the parathyroid glands, thymus, and conotruncal region of the heart. Shprintzen and colleagues first described the syndrome in 1978.[1] More than 180 different clinical features are associated with velocardiofacial syndrome, with no single anomaly present in every patient. Some abnormalities are more common than others. Affected individuals may present with structural or functional palatal abnormalities, cardiac defects, unique facial characteristics, hypernasal speech, hypotonia, and defective thymic development.
An estimated 75% of patients with velocardiofacial syndrome have cardiac anomalies.[2] The cardiac defects are usually of the conotruncal type, which occur secondary to abnormal development of the outflow portion of the developing heart. The most common cardiac defects include interrupted aortic arch type B (50%), truncus arteriosus (34.5%) and tetralogy of Fallot (16%). Other cardiac defects include pulmonary atresia with ventricular septal defect, absent pulmonary valve syndrome, ventricular septal defect (especially when accompanied by aortic arch anomalies), aortic stenosis, anomalies of the aortic arch or its major branches, and pulmonary artery anomalies.[3] D-transposition of the great arteries is rare.
Palatal abnormalities predispose to speech and feeding difficulties.
The defective thymic development is associated with impaired immune function. This condition not only predisposes to an increased risk of infection but also predisposes some individuals to develop autoimmunity. Parathyroid and immune deficiencies can progress or resolve with time.
In addition, affected individuals may present with learning disabilities, overt developmental delay, psychiatric disorders, and renal and musculoskeletal defects.
Ophthalmologic abnormalities are seen in 70% of patients with velocardiofacial syndrome, such as posterior embryotoxon, bilateral cataracts, tortuous retinal vessels, and small optic disks. Other rare anomalies include congenital absence of the nasolacrimal duct.[4]
About 10% of patients with velocardiofacial syndrome have DiGeorge syndrome, which consists of at least 2 of the following features:
- Conotruncal cardiac anomaly
- Hypoparathyroidism, hypocalcemia
- Thymic aplasia, immune deficiency
As many as 15-20% of patients have Pierre Robin syndrome, which includes small jaw, U-shaped cleft palate, and glossoptosis. Reports indicate that some patients with velocardiofacial syndrome may be mistakenly categorized as having CHARGE syndrome (ie, coloboma, heart defect, atresia choanae, retarded growth and development, and/or CNS anomalies, genital hypoplasia, and ear anomalies and/or deafness). Velocardiofacial syndrome is a specific syndrome that includes as part of its phenotypic spectrum the DiGeorge sequence, the Pierre Robin sequence, and disorders associated with CHARGE syndrome.
Pathophysiology
This congenital disorder is caused by a deletion (microdeletion) at the q11.2 band, which is located on the long arm (q) of chromosome 22 (see the images below). This microdeletion causes an abnormality of morphogenesis that, in part, affects the migration of the neural crest cells and the early development of branchial arches.
Chromosomal fluorescence in situ hybridization (FISH) demonstrating the deletion of one chromosomal region 22q11 segment. 
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. In 90% of cases, the disorder occurs as the result of a new mutation in the form of a de-novo 3-megabase microdeletion or translocation. This 3-megabase microdeletion encompasses a region that contains 40 genes.[5] These genes have a role in organ development, including the heart and the CNS. These genes likely affect coronary artery development, given the number of coronary artery abnormalities associated with conotruncal defects.[6]
In 10% of cases, the disorder is inherited from a parent in an autosomal dominant fashion.
The 22q11.2 microdeletion is more common in patients with aortic arch or major aortic branch vessel or pulmonary vessel anomalies.[3] Therefore, these patients should undergo genetic testing. However, a wide spectrum of clinical findings is reported among subjects with the 22q11.2 deletion, without genotype or phenotype correlation, even among affected family members and between patients with identical deletions.[7, 8]
Patients have a 50% chance of passing velocardiofacial syndrome to each offspring. The microdeletion is detectable with current cytogenetic and fluorescence in situ hybridization (FISH) techniques.
Epidemiology
Frequency
United States
The prevalence of velocardiofacial syndrome in the United States is approximately 1:2,000.[5]
International
Velocardiofacial syndrome 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 velocardiofacial syndrome 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.
Abnormal vessel course can increase morbidity. For example, 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. An anomalously oriented ascending aorta may cause severe left main bronchus obstruction secondary to external compression.[9]
Complete DiGeorge syndrome with total absence of the thymus and a severe T-cell immunodeficiency accounts for less than 0.5% of patients with velocardiofacial syndrome. Instead, most patients with 22q11.2 deletion syndromes have partial defects with impaired thymic development with variable defects in T-cell numbers. In these patients, immunodeficiency may also be secondary to proliferative responses. In addition, humoral deficiencies have also been identified, and this particular group of patients is at increased risk of developing various autoimmune diseases.[8] Patients with sufficient CD4(+) T cells but low numbers of cytotoxic CD3(+)CD8(+) T cells are more susceptible to noncardiac mortality secondary to lymphoproliferative disorders and lethal infections.[10]
Race
No racial predilection is noted.
Sex
No sexual predilection is observed.
Age
Velocardiofacial syndrome 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.
Shprintzen RJ, Goldberg RB, Lewin ML, et al. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J. Jan 1978;15(1):56-62. [Medline].
Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. Oct 1997;34(10):798-804. [Medline].
Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol. Aug 1998;32(2):492-8. [Medline].
Prabhakaran VC, Davis G, Wormald PJ, Selva D. Congenital absence of the nasolacrimal duct in velocardiofacial syndrome. J AAPOS. Feb 2008;12(1):85-6. [Medline].
Shprintzen RJ. Velo-cardio-facial syndrome: 30 Years of study. Dev Disabil Res Rev. 2008;14(1):3-10. [Medline].
Theveniau-Ruissy M, Dandonneau M, Mesbah K, et al. The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning. Circ Res. Jul 18 2008;103(2):142-8. [Medline].
Cuneo BF. 22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes. Curr Opin Pediatr. Oct 2001;13(5):465-72. [Medline].
McLean-Tooke A, Spickett GP, Gennery AR. Immunodeficiency and autoimmunity in 22q11.2 deletion syndrome. Scand J Immunol. Jul 2007;66(1):1-7. [Medline].
Li MJ, Wang CC, Chen SJ, et al. Anomalous ascending aorta causing severe compression of the left bronchus in an infant with ventricular septal defect and pulmonary atresia. Eur J Pediatr. Mar 2009;168(3):351-3. [Medline].
Eberle P, Berger C, Junge S, et al. Persistent low thymic activity and non-cardiac mortality in children with chromosome 22q11.2 microdeletion and partial DiGeorge syndrome. Clin Exp Immunol. Feb 2009;155(2):189-98. [Medline].
Robin NH, Taylor CJ, McDonald-McGinn DM, et al. Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation. Am J Med Genet A. Nov 15 2006;140(22):2416-25. [Medline].
Sundram F, Murphy DG, Murphy KC. White matter microstructure in children with Velocardiofacial Syndrome: A Diffusion Tensor Imaging and Voxel Based Morphometry study. J Intellect Disabil Res. Oct 2008;52(10):812. [Medline].
Antshel KM, Fremont W, Kates WR. The neurocognitive phenotype in velo-cardio-facial syndrome: a developmental perspective. Dev Disabil Res Rev. 2008;14(1):43-51. [Medline].
Carotti A, Digilio MC, Piacentini G, Saffirio C, Di Donato RM, Marino B. Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome. Dev Disabil Res Rev. 2008;14(1):35-42. [Medline].
McDonald-McGinn DM, Zackai EH. Genetic counseling for the 22q11.2 deletion. Dev Disabil Res Rev. 2008;14(1):69-74. [Medline].
Chow EW, Bassett AS, Weksberg R. Velo-cardio-facial syndrome and psychotic disorders: implications for psychiatric genetics. Am J Med Genet. Jun 15 1994;54(2):107-12. [Medline].
De Smedt B, Swillen A, Ghesquiere P, et al. Pre-academic and early academic achievement in children with velocardiofacial syndrome (del22q11.2) of borderline or normal intelligence. Genet Couns. 2003;14(1):15-29. [Medline].
Digilio MC, Angioni A, De Santis M, et al. Spectrum of clinical variability in familial deletion 22q11.2: from full manifestation to extremely mild clinical anomalies. Clin Genet. Apr 2003;63(4):308-13. [Medline].
Driscoll DA, Spinner NB, Budarf ML, et al. Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet. Sep 15 1992;44(2):261-8. [Medline].
Dyce O, McDonald-McGinn D, Kirschner RE, et al. Otolaryngologic manifestations of the 22q11.2 deletion syndrome. Arch Otolaryngol Head Neck Surg. Dec 2002;128(12):1408-12. [Medline].
Goldberg R, Motzkin B, Marion R, et al. Velo-cardio-facial syndrome: a review of 120 patients. Am J Med Genet. Feb 1 1993;45(3):313-9. [Medline].
Goldmuntz E. DiGeorge syndrome: new insights. Clin Perinatol. Dec 2005;32(4):963-78, ix-x. [Medline].
Kelly D, Goldberg R, Wilson D, et al. Confirmation that the velo-cardio-facial syndrome is associated with haplo-insufficiency of genes at chromosome 22q11. Am J Med Genet. Feb 1 1993;45(3):308-12. [Medline].
Mehendale FV, Sommerlad BC. Surgical significance of abnormal internal carotid arteries in velocardiofacial syndrome in 43 consecutive hynes pharyngoplasties. Cleft Palate Craniofac J. Jul 2004;41(4):368-74. [Medline].
Saitta SC, Harris SE, Gaeth AP, et al. Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum Mol Genet. Feb 15 2004;13(4):417-28. [Medline].
Shprintzen RJ, Goldberg RB, Young D, Wolford L. The velo-cardio-facial syndrome: a clinical and genetic analysis. Pediatrics. Feb 1981;67(2):167-72. [Medline].
Print
