Velocardiofacial Syndrome

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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 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] 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. Parathyroid and immune deficiencies can progress or resolve with time. [4, 5]

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. [6]

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.

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.

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. [7] 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. [8]

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. [9, 10, 11]

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.

United States

The prevalence of velocardiofacial syndrome in the United States is approximately 1:2,000. [7]

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%.

Those 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. [12]

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. [10] 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. [13]

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

No racial predilection is noted.

No sexual predilection is observed.

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. 1978 Jan. 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. 1997 Oct. 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. 1998 Aug. 32(2):492-8. [Medline].

Zemble R, Luning Prak E, McDonald K, McDonald-McGinn D, Zackai E, Sullivan K. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Immunol. 2010 Sep. 136(3):409-18. [Medline]. [Full Text].

Gennery AR. Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci. 2012 Jan. 69(1):17-27. [Medline].

Prabhakaran VC, Davis G, Wormald PJ, Selva D. Congenital absence of the nasolacrimal duct in velocardiofacial syndrome. J AAPOS. 2008 Feb. 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]. [Full Text].

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. 2008 Jul 18. 103(2):142-8. [Medline].

Cuneo BF. 22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes. Curr Opin Pediatr. 2001 Oct. 13(5):465-72. [Medline].

McLean-Tooke A, Spickett GP, Gennery AR. Immunodeficiency and autoimmunity in 22q11.2 deletion syndrome. Scand J Immunol. 2007 Jul. 66(1):1-7. [Medline].

Leopold C, De Barros A, Cellier C, Drouin-Garraud V, Dehesdin D, Marie JP. Laryngeal abnormalities are frequent in the 22q11 deletion syndrome. Int J Pediatr Otorhinolaryngol. 2012 Jan. 76(1):36-40. [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. 2009 Mar. 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. 2009 Feb. 155(2):189-98. [Medline].

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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. 2006 Nov 15. 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. 2008 Oct. 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].

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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. 2003 Apr. 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. 1992 Sep 15. 44(2):261-8. [Medline].

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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. 1993 Feb 1. 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. 2004 Jul. 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. 2004 Feb 15. 13(4):417-28. [Medline].

Shprintzen RJ, Goldberg RB, Young D, Wolford L. The velo-cardio-facial syndrome: a clinical and genetic analysis. Pediatrics. 1981 Feb. 67(2):167-72. [Medline].

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.

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.

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.

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 .

Jeffrey Allen Towbin, MD, MSc FAAP, FACC, FAHA, Professor, Departments of Pediatrics (Cardiology), Cardiovascular Sciences, and Molecular and Human Genetics, Baylor College of Medicine; Chief of Pediatric Cardiology, Foundation Chair in Pediatric Cardiac Research, Texas Children’s Hospital

Jeffrey Allen Towbin, MD, MSc is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Cardiology, American College of Sports Medicine, American Heart Association, American Medical Association, American Society of Human Genetics, New York Academy of Sciences, Society for Pediatric Research, Texas Medical Association, Texas Pediatric Society, Cardiac Electrophysiology Society

Disclosure: Nothing to disclose.

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.

Velocardiofacial Syndrome

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