Velocardiofacial Syndrome

Updated: Dec 15, 2020

Author: M Silvana Horenstein, MD; Chief Editor: Howard S Weber, MD, FSCAI

Overview

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 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).

Pathophysiology

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 fluorescence in situ hybridization (FISH) demonstrating the deletion of one chromosomal region 22q11 segment.

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]

Etiology

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]

Epidemiology

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.

Prognosis

Morbidity/mortality

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

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.

Presentation

History

Clinical presentation of velocardiofacial syndrome (VCFS) is highly variable, ranging from severe and detected at birth to very subtle (it may only be recognized later in life) depending on the cardiac defect present.

Cyanosis may be present in individuals with VCFS with certain cardiac defects, such as truncus arteriosus or tetralogy of Fallot. Neonates with an interrupted aortic arch may present with tachypnea, poor feeding, lethargy, or cardiogenic shock if prostaglandins are not initiated promptly.

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 (VPI). 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.[16]

Developmental delay in infants with a learning disorder becomes apparent in childhood. Attention deficit hyperactivity disorder (ADHD) occurs in 35-55% of persons with velocardiofacial syndrome.[12]

Poor social interaction or behavioral difficulties are common. Psychiatric disorders (including obsessive-compulsive disorder and schizophrenia) are reported in at least 10% of patients.[14, 24]

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. Twenty-five to 50% of these children fall below the second percentile for all growth parameters.[15]

Typical facial features include a bulbous-tipped nose, micrognathia, and malar flattening.[2]

Physical Examination

Cyanosis may be present in a patient with velocardiofacial syndrome (VCFS) if an obligate systemic-to-pulmonic (right-to-left) shunt is present.

A heart murmur is present in most patients with a cardiac defect.

Craniofacial dysmorphism is often 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 velocardiofacial syndrome.

DDx

Diagnostic Considerations

Important considerations

Upon suspecting velocardiofacial syndrome (VCFS), perform the following:

Perform chromosome testing
Test the chromosomes of the parents or children of the affected person
Give appropriate genetic counseling
Use irradiated cell blood products (to avoid risk of transfusion acquired graft-versus-host disease by transfused lymphocytes)

Special concerns

The following are special concerns:

Consider the possibility of VCFS in any fetus diagnosed with conotruncal heart disease on prenatal ultrasound
To make a prenatal diagnosis, perform amniocentesis for cytogenetic and fluorescence in situ hybridization (FISH) testing
Considerable variability in manifestations is noted among affected family members

Differential Diagnoses

Workup

Laboratory Studies

It is recommended that infants born with interrupted aortic arch type B or other isolated aortic arch anomalies, as well as those with truncus arteriosus or tetralogy of Fallot, undergo genetic testing to detect a 22q11.2 deletion.

High-resolution (650 band level and above) chromosome analysis is used to look for a chromosome region 22q11.2 deletion.

Fluorescence in situ hybridization (FISH) for a band 22q11.2 deletion must be performed to rule out a submicroscopic deletion (see the image below).

Velocardiofacial Syndrome. Chromosomal fluorescence in situ hybridization (FISH) demonstrating the deletion of one chromosomal region 22q11 segment.

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.

Serum calcium levels should be measured in diagnosed newborns and in any patients with suspected velocardiofacial syndrome (VCFS) at any age who have seizures.

Immunologic studies (T-cell marker studies) should be performed as directed by a pediatric immunologist on all infants with this diagnosis and in older individuals who have a history of frequent infections.

Genetic testing serves to identify those individuals affected by the 22q11.2 deletion and, therefore, identifying the need for present and future medical attention.

Other Tests

Electrocardiography (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.

Imaging Studies

Chest radiography can reveal evidence of a heart defect in a patient with velocardiofacial syndrome (VCFS).

Echocardiography 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 magnetic resonance imaging (MRI) is used if a severe delay is present. Numerous brain malformations have been observed in these patients, such as pachygyria or polymicrogyria, agenesis of the corpus callosum, myelomeningocele, and mild cerebellar hypoplasia or mega cisterna magna (the latter two are the most common).[10] Of note, young patients with VCFS have significant differences in white matter microstructure and volume, and some of these defects seem to be associated with schizotypal behavior.[11, 25]

Procedures

As stated earlier, the most common cardiac malformations in patients with velocardiofacial syndrome (VCFS) include conotruncal defects, such as tetralogy of Fallot (TOF), pulmonary atresia with ventricular septal defect (PA-VSD), truncus arteriosus (TA), interrupted aortic arch (IAA), and ventricular septal defect (VSD). Cardiac catheterization is usually not necessary for diagnosis, as an echocardiogram will show the cardiac structures; however, it might be indicated to evaluate and treat specific cardiac lesions, such as stenotic pulmonary arteries where flow may be severely restricted.

Treatment

Medical Care

Evaluation of patients with velocardiofacial syndrome (VCFS) usually occurs in the outpatient setting where workup for other associated problems is requested as needed.

In newborns, however, the diagnosis may be made in the hospital, either at the bedside if the diagnosis was known prior to birth through a fetal echocardiogram or suspected after birth due to cyanosis. Newborns with or without associated heart defects may still require a prolonged hospitalization secondary to feeding difficulties.

Medical therapy may be required to treat heart failure, hypocalcemia, immune deficiency, feeding problems, and inadequate growth. Medications may be required for specific abnormalities in patients with VCFS as indicated (see "Other Problems to be Considered" in the DDx section).

Neurocognitive issues associated with VCFS during infancy and preschool years, feeding problems, cleft palate, and developmental disorders occupy most of the clinical management in these patients. During school years, management shifts to cognitive, behavioral, and learning disorders. The most common cognitive finding in these patients is their functioning within the low-borderline range. Related features include significant visuospatial dysfunction,[26] diminished math attainment, and executive dysfunction. In late adolescence and adult years, psychiatric illness such as schizophrenia or bipolar disorder become more of a concern because these may develop in 10% of adults with this condition.[12]

Transfer

Newborns who require cardiac surgery may need transfer to a tertiary center.

Diet and activity

No special diet is required, except as indicated for cardiac disease, feeding problems, growth problems, or other abnormalities.

Usually no restrictions are needed, except as indicated for cardiac disease or other abnormalities.

Consultation

Consultation with the following specialists may be indicated:

Pediatric cardiologist
Cardiothoracic surgeon
Plastic surgeon (cleft palate)
Endocrinologist
Otolaryngologist
Ophthalmologist
Pediatrician (developmental)
Psychiatrist
Medical geneticist

Surgical Care

At the time of surgery for patients with velocardiofacial syndrome (VCFS), the complex cardiovascular anatomy in association with depressed immunological status, pulmonary vascular reactivity, neonatal hypocalcemia, bronchomalacia and bronchospasm, laryngeal web, and tendency for airway bleeding must be considered.[27]

Irradiated cell blood products should be used in patients susceptible to developing graft versus host disease; if the immune status of the patient is not known, irradiated cell blood products must be used.

A cleft palate should be repaired.

Pharyngeal flap surgery may be required to treat velopharyngeal incompetence (VPI) and improvement in hypernasality; in planning the surgery, consider that the internal carotid is commonly medially displaced and tortuous. Note that thinned levator veli muscle in patients with velocardiofacial syndrome patients appears to be associated with widened velopharyngeal gap and production of hypernasal speech, and thus negatively impact postoperative surgical outcome of pharyngeal flap surgery.[28]

Ventilation of ear tubes may be indicated.

Author

M Silvana Horenstein, MD Assistant Professor, Department of Pediatrics, University of Texas Medical School at Houston; Medical Doctor Consultant, Legacy Department, Best Doctors, Inc

M Silvana Horenstein, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Robert Ardinger, Jr, MD Associate Professor, Department of Pediatrics, Division of Pediatric Cardiology, University of Kansas Medical Center

Robert Ardinger, Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology

Disclosure: Nothing to disclose.

Holly Ardinger, MD Clinical Associate Professor, Section Chief, Pediatric Genetics, Department of Pediatrics, University of Kansas Medical Center

Holly Ardinger, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Ameeta Martin, MD Clinical Associate Professor, Department of Pediatric Cardiology, University of Nebraska College of Medicine

Ameeta Martin, MD is a member of the following medical societies: American College of Cardiology

Disclosure: Nothing to disclose.

Chief Editor

Howard S Weber, MD, FSCAI Professor of Pediatrics, Section of Pediatric Cardiology, Pennsylvania State University College of Medicine; Director of Interventional Pediatric Cardiology, Penn State Hershey Children's Hospital

Howard S Weber, MD, FSCAI is a member of the following medical societies: Society for Cardiovascular Angiography and Interventions

Disclosure: Received income in an amount equal to or greater than $250 from: Abbott Medical .

Acknowledgements

Thomas J Forbes, MD, FACC, FSCAI Associate Professor (Clinical-Educator), Director of Catheterization Laboratory, Division of Pediatric Cardiology, Children's Hospital of Michigan, Wayne State University

Thomas J Forbes, MD, FACC, FSCAI is a member of the following medical societies: American College of Cardiology, American Heart Association, and Society of Cardiac Angiography and Interventions

Disclosure: Nothing to disclose.

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