Velocardiofacial Syndrome

Updated: Dec 15, 2020
  • Author: M Silvana Horenstein, MD; Chief Editor: Howard S Weber, MD, FSCAI  more...
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Velocardiofacial syndrome (VCFS) is a genetic condition characterized by abnormal pharyngeal arch development that results in defective development of the parathyroid glands, thymus, and the conotruncal region of the heart. Shprintzen and colleagues first described the syndrome in 1978. [1]  Its genetic cause is a microdeletion of chromosome 22 at band q11.2.

VCFS includes as part of its phenotypic spectrum the DiGeorge  sequence, the Pierre Robin  sequence, the CATCH-22 association  (which is a medical acronym for Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcemia), and disorders associated with CHARGE syndrome  (another medical acronym for Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital and urinary abnormalities, and Ear abnormalities and/or hearing loss). These are all different names to describe phenotypic variants  of the VCFS  [2]

More than 180 different clinical features are associated with VCFS, in which almost any organ can be affected. [2] 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. [3]

An estimated 75% of patients with VCFS have cardiac anomalies. [4] 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. [5] The presence of an aortic arch anomaly increases the odds of having a 22q11.2 deletion, regardless of the intracardiac anatomy.

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. [6, 7] Parathyroid and immune deficiencies can progress or resolve with time. [8, 9]

In addition, affected individuals may present with learning disabilities, overt developmental delay, [10, 11, 12, 13]  psychiatric disorders, [14]  and renal and musculoskeletal defects. [15]

Ophthalmologic abnormalities are seen in 70% of patients with velocardiofacial syndrome, such as posterior embryotoxon, bilateral cataracts, tortuous retinal vessels, and small optic disks. [16]  Other rare anomalies include congenital absence of the nasolacrimal duct. [17]

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 (VCFS) 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.

Velocardiofacial Syndrome. Chromosomal fluorescenc Velocardiofacial Syndrome. Chromosomal fluorescence in situ hybridization (FISH) demonstrating the deletion of one chromosomal region 22q11 segment.
Velocardiofacial Syndrome. Karyotype of a patient Velocardiofacial Syndrome. Karyotype of a patient with a deletion of chromosome region 22q11. The 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 three-megabase microdeletion encompasses a region that contains 40 genes. [2] These genes have a role in organ development, including the heart and the central nervous system (CNS). These genes likely affect coronary artery development, given the number of coronary artery abnormalities associated with conotruncal defects. [18]  

In 10% of cases, the disorder is inherited from a parent in an autosomal dominant fashion. Such patients thus have a 50% chance of passing VCFS to each offspring. [19] The microdeletion is detectable with current cytogenetic and fluorescence in situ hybridization (FISH) techniques. 

The 22q11.2 microdeletion is more common in patients with aortic arch or major aortic branch vessel or pulmonary vessel anomalies. [5] 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. [20, 6, 21]



Most patients with velocardiofacial syndrome (VCFS) have a microdeletion at the q11.2 locus of the long arm of chromosome 22. Most cases are the result of a de novo microdeletion, with approximately 10% of patients inheriting this deletion from a parent. When such microdeletion is inherited, the recurrence risk is 50%, and penetrance is 10 %, although with marked phenotypical variability. [22]

The above referenced 22q11.2 deletion usually occurs during meiosis by nonallelic homologous recombinations (NAHR) between low copy repeats (LCR) on chromosome 22q11.2 (LCR22). In more detail, in 90% of cases, the region between LCR22A-D is deleted. The second most common deletion occurs between LCR22A-B, and the least common deletion occurs between LCRA-C on chromosome 22q11.2. [22]



United States data

The prevalence of velocardiofacial syndrome in the United States is approximately 1:2,000. [2]

International data

Velocardiofacial syndrome occurs in 1:4,000 to 1:7,000 births worldwide, [2]  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%.

Race-, sex-, and age-related demographics

No racial or sexual predilection is noted.

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.




Those with velocardiofacial syndrome (VCFS) but without serious heart defects can expect a normal lifespan.

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. [23]

Complete DiGeorge syndrome with total absence of the thymus and a severe T-cell immunodeficiency accounts for less than 0.5% of patients with VCFS. 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. [6]  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. [7]


Complications include the following:

  • Congestive heart failure

  • Pulmonary hypertension

  • Immune deficiency (cellular and humoral) with increased risk of infection and autoimmune diseases

  • Psychiatric disorders


Patient Education

Genetic counseling of the patient and family should emphasize that most deletions are de novo, secondary to homologous recombination between low copy repeat sequences located within 22q11.2. [22]  Nonetheless, both somatic and germline mosaicism can also occur, conferring unaffected parents a small risk of recurrence. However, once present, velocardiofacial syndrome (VCFS) is dominant, and children of the patient have a 50% risk of being affected; children can be affected more severely or less severely than the parent. [19]

Prenatal diagnosis is available to detect the chromosome region 22q11.2 deletion.

For patient education resources, see the Heart Health Center, as well as Tetralogy of Fallot.