Current perspectives on velocardiofacial syndrome

Saikrishna Lakkakula; Ulaganathan Baraneedharan; Bhaskar V. K. S. Lakkakula

doi:10.4103/bbrj.bbrj_63_17

REVIEW ARTICLE

Year : 2017 | Volume : 1 | Issue : 2 | Page : 101-104

Current perspectives on velocardiofacial syndrome

Saikrishna Lakkakula¹, Ulaganathan Baraneedharan², Bhaskar V. K. S. Lakkakula³
¹ Department of Zoology, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
² Division of Cancer Biology, Mitra RxDx Inc, Woburn, MA 01801, USA
³ Department of Molecular Genetics, Sickle Cell Institute Chhattisgarh, Raipur, Chhattisgarh, India

Date of Web Publication

23-Nov-2017

Correspondence Address:
Bhaskar V. K. S. Lakkakula
Sickle Cell Institute Chhattisgarh, Pt. JNM Medical College, Raipur, Chhattisgarh
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_63_17

Abstract

Velocardiofacial syndrome (VCFS) is one of the most common genetic disorders that affect every major system in the body. The worldwide frequency of VCFS is 1 in 2000 live births. A search using the terms and variants of velo-cardio facial syndrome, VCFS, and disabilities within PubMed, Embase, and Scopus was carried out and restricted to human studies published in English. Further, reference lists were checked to identify relevant studies. The phenotypic spectrum of VCFS overlaps with that of DiGeorge syndrome and includes physical, cognitive, behavioral, and neurological disabilities. The VCFS is caused by hemizygous deletions on chromosome 22q11.2 and usually diagnosed at childhood. Several approaches, such as fluorescence in situ hybridization and polymerase chain reaction-based techniques, have been applied to analyze deleted regions. As majority of the VCFS children have multiple diagnoses, it may need more time to find appropriate combination of medications that will work for them. Treatment for VCFS is always depended on child's age, overall health, medical history, and child's tolerance for specific medications, procedures, or therapies, and parents' opinion or preference.

Keywords: 22q11 deletion, digeorge anomaly, signs and symptoms, velocardiofacial syndrome

How to cite this article:
Lakkakula S, Baraneedharan U, Lakkakula BV. Current perspectives on velocardiofacial syndrome. Biomed Biotechnol Res J 2017;1:101-4

How to cite this URL:
Lakkakula S, Baraneedharan U, Lakkakula BV. Current perspectives on velocardiofacial syndrome. Biomed Biotechnol Res J [serial online] 2017 [cited 2021 Jan 16];1:101-4. Available from: https://www.bmbtrj.org/text.asp?2017/1/2/101/219106

Introduction

Velocardiofacial syndrome (VCFS; MIM 192430) is one of the most common genetic disorders that affect every major system in the body [Figure 1]. The worldwide frequency of VCFS is 1 in 2000 live births. The VCFS disabilities may be physical, cognitive, behavioral, and neurological.^[1],[2],[3] Cognitive deficits, problems in arithmetic calculation, or reasoning,^[4] distinct inadequacies in visuospatial memory, visual attention, and working memory were documented in the individuals with VCFS.^[5] Neurological symptoms include poor psychomotor, tactile, and perceptual skills.^[4] Development of schizophrenia during adolescence or early adulthood was reported in 15% and 25% of VCFS patients, respectively; hence, VCFS is proposed as a model for a genetically mediated subtype of schizophrenia.^[6],[7] The phenotypic spectrum of VCFS overlaps with that of DiGeorge syndrome (DGS; MIM 188400); hence, VCFS and DGS have the same molecular etiology.^[8],[9] VCFS occurs in 90% of cases from a large 3-Mb deletion on chromosome 22 (del 22q11.2).^[10],[11] Analysis of 14 simple tandem repeat markers in each patient and their unaffected parents led to the detection of the extent of the deletion in VCFS patients.^[11] For this review, a search using the combination of terms and variants of velo-cardio facial syndrome, VCFS, and disabilities within PubMed, Embase, Scopus, and directory of open access journals was carried out and restricted to human studies published in English. Further, reference lists were checked to identify the relevant studies.

Figure 1: Common clinical features and complications of velocardiofacial syndrome

Click here to view

Distribution

Given the poor survival of individuals with VCFS, the population prevalence for VCFS is not as high as incidence. The prevalence of VCFS is estimated based on the birth records, reports of infant examinations, or reports of anomalies from multiple sources that were admitted to “technical errors” and “an inadequate quality- control protocol.”^[12] However, in the world populations, the prevalence of VCFS is ranging from approximately 1:2000 to 1:7000.^[13] As VCFS patients survive better in places where good surgical care and neonatal intensive care units are available, higher prevalence was noted in developed and medically sophisticated countries compared to developing or undeveloped countries.^[12]

Physical Features

The physical features of VCFS individuals include extended face, tiny ears with over-furled helices, upslanting eyes, a broadened nasal bridge with a prominent nasal tip, and a petite mouth with cleft palate and/or cleft lip. Further, patients with VCFS have several symptomatic cardiac malformations.

Behavioral Features

Behavioral excitation is the main feature of VCFS and they exhibit an extravagant response to hostile stimuli, and in both children and adolescents, a long-term fearfulness of repeated painful episodes was documented.^[14] In addition, children with VCFS are reported to have poor social relations with minimal facial expression, attention-deficit, and high intensity of disquiet and depression.^[15],[16] Several studies also reported high rates of bipolar disorder, attention-deficit/hyperactive disorder, and psychosis in VCFS individuals.^{[1],[2],[17],[18]}

Neuropsychological Deficits

Neuropsychological deficits among the VCFS children include language abnormalities such as immature language usage, poor development of numeric skills, and significant impairments in reading and spelling.^[14] On tests of general intellectual functioning, the verbal intelligence quotient (IQ) exceeds performance IQ in the children with VCFS.^[16],[19] These variations in IQ reflect the problems in planning capability, visuospatial capacity, and concept construction.

Brain Structural Anomalies

Although the biological determinants of the neurocognitive and behavioral features of VCFS are not yet fully understood, this disorder has measurable effects on brain structure and function.^{[20],[21],[22],[23],[24],[25]} Quantitative neuroimaging studies revealed decreased gray and white matter volumes in parietal lobe and frontal lobe.^{[22],[24],[26],[27]} Dissimilarities that observed in the construction of regional white matter tracts in VCFS adults reflected the variations in the volumes of the frontal, parietal, and temporal lobes.^[26],[28] Observation of brain activation made during an arithmetic task in VCFS demonstrated an uncharacteristic functional stimulation in the left parietal region leading to deficiencies in arithmetic reasoning and parietal lobe function.^[29] Analyses of gyrification have suggested that early abnormal connectivity is likely to change initial cortical morphology.^[30],[31] This may explain numerous reports of cortical dysgenesis in patients with VCFS.^{[32],[33],[34]}

Etiology

VCFS is a genetic condition and all of the genes that cause VCFS have not been identified. Nearly 85% of VCFS patients and 10%–30% of patients with isolated conotruncal defects carry a microdeletion on the long arm of one copy of chromosome 22 at band q11.2.^[35],[36] The deletion at 22q11.2 segregates as autosomal dominant fashion that results in a haploinsufficiency of products encoded by genes within the deleted region. As the 22q11 region is susceptible to rearrangements, the deletions occur as sporadic in nature. It was also demonstrated that 83% of the patients had a detec[table 22]q11 deletion [Figure 2]. Haplotype analysis revealed that 90% of the VCFS patients with a deletion had a similar 3-Mb deletion.^[11] Studies using fluorescence in situ hybridization (FISH) also revealed that the VCFS/DGS region on 22q11 was bordered by low-copy repetitive sequences.^[37] Constructing high-resolution physical maps in the interval sequences of the proximal and distal end of 3 Mb breakpoints also revealed the presence of low-copy repetitive sequences and designated them “VCFS-REPs.”^[38]{table 22}

Figure 2: Deletions reported from chromosome 22 and velocardiofacial syndrome

Click here to view

Diagnosis

Although the VCFS can be predicted by physical examination and family history, the exact diagnostic procedure includes blood tests and other tests to examine the immune system problems.^[39] X- rays of the body, its organs, and other internal structures are useful to diagnose the problem. Echocardiography evaluates the structure and condition of heart valves. Conotruncal heart defects, clefting, other facial features, hypocalcemia, and thymus lacking are identified. The microdeletion of chromosome 22q11.2 is not visible by conventional cytogenetic analysis, but detectable by FISH which can detect smaller deletions or duplications.^[40] If a 22q11 deletion is detected in a child, then both parents should be tested for deletion to see if this deletion is hereditary or sporadic. The 22q11 deletion was detected in at least one of the parents in approximately 10% of families and shows an inheritance risk of 50% with each pregnancy. The standard FISH technique is time-consuming, laborious, costly, and put up with the significant limitation that some patients with uniquely localized microdeletions or duplications may yield normal clinical FISH findings because the probe set used does not map precisely to the entire region of deletions/duplication. If the FISH test fails to detect no deletion in 22q11 region and the characters of VCFS are still strikingly indicative, comparative genomic hybridization technique should be executed to probe for other chromosomal abnormalities. Currently, DNA arrays providing full coverage of the human genome are widely available to diagnostically screen large number of patients.^[41]

As an alternative to the FISH technique,^[40] a semi-quantitative polymerase chain reaction (PCR) can be used.^[42] For this assay, exon 5 of catechol-O-methyltransferase (COMT) (deleted in VCFS cases) on chromosome 22 and exon 11 of the ATP-binding cassette subfamily G member 1 (ABCG1) gene on chromosome 21 regions should be simultaneously amplified in the same reaction. Screening of both ABCG1 and COMT has revealed that there are no common polymorphisms within these fragments that can interfere with the reaction.^[43],[44] If a person has a single copy of COMT, the ratio of COMT/ABCG1 is ~50% than that of the ratio obtained from an individual with two copies of COMT.^[45] Real-time quantitative PCR approach was reported as an accurate method for the detection of chromosomal microdeletions and microduplications.^[46]

Intervention and Treatment

A small percentage of 22q11 deletion children with severe heart defects and immune system problems will not survive the 1^st year of life. With the appropriate management, these children will survive and mature into adulthood. However, they need support during schooling and will need long-term assistance for their specific health requirements. Early intervention in improving muscle strength, mental stimulation, and speech problems will help the VCFS. Evaluation of heart defects by a cardiologist, correction of cleft lip and/or palate by a plastic surgeon and speech pathologist, assessment of feeding difficulties by gastrointestinal specialists will help in the management of VCFS.^[47] Treatment for VCFS is always depends on child's age, overall health, medical history, and child's tolerance for specific medications, procedures, or therapies, and parents opinion or preference.

Conclusion

As the complications of VCFS are broad, parents need to identify, understand, and learn how to cope with the affected child. Further, if any symptoms related to behavioural and emotional problems are seen, a psychiatric professional help should be sought right away. Furthermore, if any VCFS patient has schizophrenia and other psychiatric illness, it is required to treat with available medications that inhibit COMT gene to improve cognition and perhaps reduce illness severity. However, a majority of the VCFS children have multiple diagnoses and need more time to find a combination of medications that will work for them.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999;56:940-5.
2.	Pulver AE, Nestadt G, Goldberg R, Shprintzen RJ, Lamacz M, Wolyniec PS, et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis 1994;182:476-8.
3.	Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW. Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 1992;42:141-2.
4.	Swillen A, Vandeputte L, Cracco J, Maes B, Ghesquière P, Devriendt K, et al. Neuropsychological, learning and psychosocial profile of primary school aged children with the velo-cardio-facial syndrome (22q11 deletion): Evidence for a nonverbal learning disability? Child Neuropsychol 1999;5:230-41.
5.	Sobin C, Kiley-Brabeck K, Karayiorgou M. Associations between prepulse inhibition and executive visual attention in children with the 22q11 deletion syndrome. Mol Psychiatry 2005;10:553-62.
6.	Bassett AS, Chow EW. 22q11 deletion syndrome: A genetic subtype of schizophrenia. Biol Psychiatry 1999;46:882-91.
7.	Murphy KC, Owen MJ. Velo-cardio-facial syndrome: A model for understanding the genetics and pathogenesis of schizophrenia. Br J Psychiatry 2001;179:397-402.
8.	Stevens CA, Carey JC, Shigeoka AO. Di George anomaly and velocardiofacial syndrome. Pediatrics 1990;85:526-30.
9.	Trost D, Wiebe W, Uhlhaas S, Schwindt P, Schwanitz G. Investigation of meiotic rearrangements in DGS/VCFS patients with a microdeletion 22q11.2. J Med Genet 2000;37:452-4.
10.	Burn J, Goodship J. Developmental genetics of the heart. Curr Opin Genet Dev 1996;6:322-5.
11.	Carlson C, Sirotkin H, Pandita R, Goldberg R, McKie J, Wadey R, et al. Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am J Hum Genet 1997;61:620-9.
12.	Oskarsdóttir S, Vujic M, Fasth A. Incidence and prevalence of the 22q11 deletion syndrome: A population-based study in Western Sweden. Arch Dis Child 2004;89:148-51.
13.	Shprintzen RJ. Velo-cardio-facial syndrome: 30 years of study. Dev Disabil Res Rev 2008;14:3-10.
14.	Golding-Kushner KJ, Weller G, Shprintzen RJ. Velo-cardio-facial syndrome: Language and psychological profiles. J Craniofac Genet Dev Biol 1985;5:259-66.
15.	Gothelf D, Presburger G, Zohar AH, Burg M, Nahmani A, Frydman M, et al. Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome. Am J Med Genet B Neuropsychiatr Genet 2004;126B: 99-105.
16.	Swillen A, Devriendt K, Legius E, Eyskens B, Dumoulin M, Gewillig M, et al. Intelligence and psychosocial adjustment in velocardiofacial syndrome: A study of 37 children and adolescents with VCFS. J Med Genet 1997;34:453-8.
17.	Baker KD, Skuse DH. Adolescents and young adults with 22q11 deletion syndrome: Psychopathology in an at-risk group. Br J Psychiatry 2005;186:115-20.
18.	Papolos DF, Faedda GL, Veit S, Goldberg R, Morrow B, Kucherlapati R, et al. Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: Does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am J Psychiatry 1996;153:1541-7.
19.	Moss EM, Batshaw ML, Solot CB, Gerdes M, McDonald-McGinn DM, Driscoll DA, et al. Psychoeducational profile of the 22q11.2 microdeletion: A complex pattern. J Pediatr 1999;134:193-8.
20.	Chow EW, Mikulis DJ, Zipursky RB, Scutt LE, Weksberg R, Bassett AS. Qualitative MRI findings in adults with 22q11 deletion syndrome and schizophrenia. Biol Psychiatry 1999;46:1436-42.
21.	Eliez S, Blasey CM, Schmitt EJ, White CD, Hu D, Reiss AL. Velocardiofacial syndrome: Are structural changes in the temporal and mesial temporal regions related to schizophrenia? Am J Psychiatry 2001;158:447-53.
22.	Eliez S, Schmitt JE, White CD, Reiss AL. Children and adolescents with velocardiofacial syndrome: A volumetric MRI study. Am J Psychiatry 2000;157:409-15.
23.	Eliez S, Schmitt JE, White CD, Wellis VG, Reiss AL. A quantitative MRI study of posterior fossa development in velocardiofacial syndrome. Biol Psychiatry 2001;49:540-6.
24.	Kates WR, Burnette CP, Jabs EW, Rutberg J, Murphy AM, Grados M, et al. Regional cortical white matter reductions in velocardiofacial syndrome: A volumetric MRI analysis. Biol Psychiatry 2001;49:677-84.
25.	van Amelsvoort T, Daly E, Robertson D, Suckling J, Ng V, Critchley H, et al. Structural brain abnormalities associated with deletion at chromosome 22q11: Quantitative neuroimaging study of adults with velo-cardio-facial syndrome. Br J Psychiatry 2001;178:412-9.
26.	Simon TJ, Bish JP, Bearden CE, Ding L, Ferrante S, Nguyen V, et al. A multilevel analysis of cognitive dysfunction and psychopathology associated with chromosome 22q11.2 deletion syndrome in children. Dev Psychopathol 2005;17:753-84.
27.	Chow TW, Miller BL, Boone K, Mishkin F, Cummings JL. Frontotemporal dementia classification and neuropsychiatry. Neurologist 2002;8:263-9.
28.	Barnea-Goraly N, Menon V, Krasnow B, Ko A, Reiss A, Eliez S. Investigation of white matter structure in velocardiofacial syndrome: A diffusion tensor imaging study. Am J Psychiatry 2003;160:1863-9.
29.	Eliez S, Blasey CM, Menon V, White CD, Schmitt JE, Reiss AL. Functional brain imaging study of mathematical reasoning abilities in velocardiofacial syndrome (del22q11.2). Genet Med 2001;3:49-55.
30.	Dehay C, Giroud P, Berland M, Killackey H, Kennedy H. Contribution of thalamic input to the specification of cytoarchitectonic cortical fields in the primate: Effects of bilateral enucleation in the fetal monkey on the boundaries, dimensions, and gyrification of striate and extrastriate cortex. J Comp Neurol 1996;367:70-89.
31.	Van Essen DC, Drury HA. Structural and functional analyses of human cerebral cortex using a surface-based atlas. J Neurosci 1997;17:7079-102.
32.	Bird LM. Cortical dysgenesis and 22q11 deletion. Clin Dysmorphol 2001;10:77.
33.	Robin NH, Taylor CJ, McDonald-McGinn DM, Zackai EH, Bingham P, Collins KJ, et al. Polymicrogyria and deletion 22q11.2 syndrome: Window to the etiology of a common cortical malformation. Am J Med Genet A 2006;140:2416-25.
34.	Schaer M, Schmitt JE, Glaser B, Lazeyras F, Delavelle J, Eliez S. Abnormal patterns of cortical gyrification in velo-cardio-facial syndrome (deletion 22q11.2): An MRI study. Psychiatry Res 2006;146:1-11.
35.	Driscoll DA, Salvin J, Sellinger B, Budarf ML, McDonald-McGinn DM, Zackai EH, et al. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: Implications for genetic counselling and prenatal diagnosis. J Med Genet 1993;30:813-7.
36.	Goldmuntz E, Driscoll D, Budarf ML, Zackai EH, McDonald-McGinn DM, Biegel JA, et al. Microdeletions of chromosomal region 22q11 in patients with congenital conotruncal cardiac defects. J Med Genet 1993;30:807-12.
37.	Halford S, Wilson DI, Daw SC, Roberts C, Wadey R, Kamath S, et al. Isolation of a gene expressed during early embryogenesis from the region of 22q11 commonly deleted in DiGeorge syndrome. Hum Mol Genet 1993;2:1577-82.
38.	Edelmann L, Pandita RK, Morrow BE. Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am J Hum Genet 1999;64:1076-86.
39.	McDonald-McGinn DM, LaRossa D, Goldmuntz E, Sullivan K, Eicher P, Gerdes M, et al. The 22q11.2 deletion: Screening, diagnostic workup, and outcome of results; report on 181 patients. Genet Test 1997;1:99-108.
40.	Berend SA, Spikes AS, Kashork CD, Wu JM, Daw SC, Scambler PJ, et al. Dual-probe fluorescence in situ hybridization assay for detecting deletions associated with VCFS/DiGeorge syndrome I and DiGeorge syndrome II loci. Am J Med Genet 2000;91:313-7.
41.	Mockler TC, Chan S, Sundaresan A, Chen H, Jacobsen SE, Ecker JR. Applications of DNA tiling arrays for whole-genome analysis. Genomics 2005;85:1-15.
42.	Shi YR, Hsieh KS, Wu JY, Lee CC, Tsai CH, Tsai FJ. Molecular analysis of syndromic congenital heart disease using short tandem repeat markers and semiquantitative polymerase chain reaction method. Pediatr Int 2002;44:264-8.
43.	Kirov G, Lowry CA, Stephens M, Oldfield S, O'Donovan MC, Lightman SL, et al. Screening ABCG1, the human homologue of the Drosophila white gene, for polymorphisms and association with bipolar affective disorder. Mol Psychiatry 2001;6:671-7.
44.	Meloto CB, Segall SK, Smith S, Parisien M, Shabalina SA, Rizzatti-Barbosa CM, et al. COMT gene locus: New functional variants. Pain 2015;156:2072-83.
45.	Ivanov D, Kirov G, Norton N, Williams HJ, Williams NM, Nikolov I, et al. Chromosome 22q11 deletions, velo-cardio-facial syndrome and early-onset psychosis. Molecular genetic study. Br J Psychiatry 2003;183:409-13.
46.	Weksberg R, Hughes S, Moldovan L, Bassett AS, Chow EW, Squire JA. A method for accurate detection of genomic microdeletions using real-time quantitative PCR. BMC Genomics 2005;6:180.
47.	Karaagac AT, Yildirim AI. General approach to velocardiofacial anomalies: A pediatric case presenting with Fallot tetralogy. North Clin Istanb 2015;1:182-6.