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Velocardiofacial Syndrome

CATCH 22

Velocardiofacial syndrome (VCFS), also known as digeorge syndrome or 22q11.2 syndrome, is a genetic disorder characterized by malformations in the pharyngeal arch derivatives including the thymus, parathyroid glands, and the conotruncal part of the heart. 


Presentation

VCFS presents with a myriad of anomalies and clinical features which occur in different combinations in patients. Some features may present later in life, while others present at birth.

Generally, the signs and symptoms which manifest in each patient are reflective of the anomalies present; cardiac defects such as tetralogy of fallot present with cyanosis, and abnormal interruptions in the aortic arch presents with poor feeding, lethargy, tachypnea, and cardiogenic shock. Poor feeding and failure to thrive may result secondary to severe cardiac anomalies and congestive cardiac failure.

Other common cardiac defects seen in VFCS include ventricular septal defects, pulmonary atresia, truncus arteriosus, absent pulmonary valve syndrome, aortic stenosis, and abnormalities of the pulmonary artery. Generally, the defects affect the cardiac outflow tract. Abnormalities in the aortic arch are almost a typical finding in VFCS and are strongly suggestive of the 22q11.2 microdeletion. Cardiac defects are seen in three of four cases of VFCS.

Submucous cleft palate causes nasal reflux of meals in infants, and velopharyngeal incompetence causes speech defects and hypernasal speech.

Sequel to the thymic underdevelopment, there may be immune dysfunction which make the patients prone to recurrent infections and development of autoimmune diseases.

The palatal abnormality predisposes to recurrent upper respiratory tract and ear infections which exacerbate the speech difficulty. Pierre robin syndrome is seen in 15-20% of cases and it comprises of micrognathia, glossoptosis, and cleft palate.

Delay in attaining developmental milestones is also commonly seen in infants, up to 55% of which develop attention deficit hyperactivity disorder (ADHD) in childhood.

Ophthalmic involvement occurs in up to 70% of patients with VFCS and may manifest as small optic disks, tortuous retinal vessels, bilateral cataracts and absence of the nasolacrimal ducts.

Over 10% of children go on to develop psychiatric disorders including schizophrenia with antisocial personality disorders. Hypocalcemia from the parathyroid defects may cause seizures during infancy. The hypocalcemia may resolve spontaneously.

About 30% of patients with VFCS have short stature, 25-50% of whom are below the second percentile with respect to all growth parameters for the respective age [14]. Common facial features in VFCS include micrognathia, malar flattening, and a bulb shaped tip of the nose.

Short Stature
  • The main manifestations of our patient were feeding difficulties, respiratory infections, short stature, peculiar face with hypertelorism, prominent nose, abnormal ears, microstomia and crowded teeth, short broad neck and shield chest with pectus deformity[ncbi.nlm.nih.gov]
  • Learning disabilities occur often; short stature, slender hyperextensible hands and digits, scoliosis, mental retardation, inguinal hernia, auricular abnormalities, and microcephaly occur less frequently.[medical-dictionary.thefreedictionary.com]
  • Height: short stature was detected in 7 of 73 (9.6%) of the total patients; the patients with short stature were all 10 years old; the height was within the normal age in all adolescent patients.[nature.com]
  • Less frequent features include short stature, small-than-normal head ( microcephaly ), mental retardation, minor ear anomalies, slender hands and digits, and inguinal hernia.[medicinenet.com]
Plethora
  • VCFS may cause significant impairment in the quality of life of the patient because of the plethora of anomalies present.[symptoma.com]
Almond-Shaped Eyes
  • Typical facial features include a long face, small almond shaped eyes, a wide bridged nose, and malformations of the ear. Learning disabilities, including delayed speech and developmental milestones, are present in 70-90% of individuals.[genedx.com]
  • The list includes: cleft palate, usually of the soft palate (the roof of the mouth nearest the throat which is behind the bony palate); heart problems; similar faces (elongated face, almond-shaped eyes, wide nose, small ears); learning difficulties; eye[healthieryou.com]
  • […] problem that is of the conotruncal type such as the interrupted aortic arch, cases of truncus arteriosus and tetralogy of Fallot Palatal problems that predispose the child to difficulties of feeding and speech Similar facial features like having an almond-shaped[syndromespedia.com]
  • Characteristic Features Not all of these identifying features are found in each child born with VCFS: Cleft palate, usually of the soft palate Craniofacial dysmorphism (elongated face, almond-shaped eyes, wide nose, small ears) Cardiac anomalies found[cme.ucsd.edu]
  • Symptoms include: cleft palate, usually of the soft palate (the roof of the mouth nearest the throat which is behind the bony palate); heart problems; similar faces (elongated face, almond-shaped eyes, wide nose, small ears); eye problems; feeding problems[genome.gov]
Low Set Ears
  • Some of the signs of velocardiofacial syndrome are as follows: Abnormalities of the palate like cleft palate Characteristic facial features like a narrow groove of the upper lip, wide-set eyes, hypertelorism or low-set ears.[syndromepictures.com]
  • Long face with prominent upper jaw Underdeveloped lower jaw Low set ears Prominent nose with narrow nasal passages Thin upper lip with a down-slanted mouth Multiple abnormalities of the heart including ventricular septal defect (VSD), pulmonary atresia[cincinnatichildrens.org]
  • Patients No. 44 presented with palatal abnormality, immune deficiency, mild mental retardation, low set ears, and conductive hearing disturbance.[journals.plos.org]
Small Head
  • Distinct physical features sometimes associated with the syndrome include loss of muscle tone (hypotonia), small slender stature, tapered hands and fingers, small head circumference (microcephaly), recessed jaw (retrognathia), tubular nose, flat cheeks[rarediseases.org]
  • Additional common traits include feeding problems, developmental delay, microcephaly (small head size) and psychiatric disorders (such as bipolar disorder and schizophrenia).[kidsplasticsurgery.org]
  • What follows are the most common features of Velo-Cardio-Facial syndrome: Feeding Difficulties Microcephaly, or a small head Hearing loss, or abnormal ear exams Hypocalcemia, or low blood calcium levels IQ levels that are usually in the 70 to 90 range[disabled-world.com]
Kidney Failure
  • Failure 1619 Pathophysiology of Progressive Renal Disease 1631 Management of Chronic Kidney Disease 1661 Handling of Drugs in Children with Abnormal Renal Function 1693 Endocrine and Growth Disorders in Chronic Kidney Disease 1713 Chronic Kidney Disease[books.google.it]
Delayed Milestone
  • Many infants present with generalized hypotonia and delayed milestones. There are psychological consequences with the reduction of full-scale intelligence quotient.[clinicaladvisor.com]
Apraxia
  • , and children with velocardiofacial syndrome demonstrated the most apraxia characteristics.[ncbi.nlm.nih.gov]
Dysmetria
  • His physical examination showed the characteristic facies of velocardiofacial syndrome as well as dysmetria and dysdiadocho-kinesia consistent with cerebellar degeneration. Molecular cytogenetic studies showed a deletion of 22q11.2.[ncbi.nlm.nih.gov]

Workup

Infants with congenital cardiac anomalies such as interrupted aortic arch type B or other aortic arch malformations and great vessel anomalies should undergo genetic testing for the 22q11.2 microdeletion. This can be carried out by using the fluorescence in situ hybridization (FISH) method. This deletion is seen in over 95% of patients with VFCS. However, those cases in which this typical microdeletion is not detected, more advanced gene testing techniques such as comparative genomic hybridization (MLPA) may be employed to detect smaller gene mutations in the same region.

Mosaicism in which not all cells are affected by the mutation can also occur in VFCS. Patients exhibiting mosaicism may present with no symptoms at all. Generally, all parents whose children have this deletion detected in all or some cells should undergo genetic testing. Furthermore, all newborns diagnosed with VFCS should have their serum calcium levels checked and monitored. This is also recommended in any child with seizures in whom VFCS is suspected.

Immunological investigations such as T-cell marker analysis may be necessary to determine and monitor the immune status.

Treatment

Diagnosis of VFCS can be made by physical examination of infants and older children on outpatient basis. Neonates may be examined after delivery for features typical of this syndrome.

Once a diagnosis is made, investigations for serious anomalies such as cardiac defects should be commenced. Heart failure, immune deficiency, feeding difficulties, and failure to thrive can all be addressed with medical care.

Generally, VFCS requires a long-term multidisciplinary management approach involving a team comprising clinical psychologist, geneticist, genetic counsellor, physical therapist, plastic surgeon, pediatric immunologist, otorhinolaryngologist, and cardiac surgeon.

Management for infants and preschoolers is usually centered on correcting feeding difficulties and developmental delays, however, in children of school age, treatment is centered on cognitive and behavioral improvement. Common cognitive impairments associated with VFCS include diminished mathematical skills, visuospatial and executive impairments.

About 10% of children with VFCS develop severe personality and psychiatric disorders [15].

Prognosis

VCFS may cause significant impairment in the quality of life of the patient because of the plethora of anomalies present. Hearing defects, speech difficulties, learning disabilities, feeding difficulties, spinal deformities, and immune compromise play significant roles in reducing the quality of life of the patient. Other factors which could worsen the prognosis of this syndrome are the secondary ophthalmic, renal, cardiac, and psychiatric problems.

Etiology

The most cases of velocardiofacial syndrome occur as a result of a microdeletion at the locus q11.2 of the short arm of chromosome 22, caused by mainly due to imbalance during the translocation between the pair of chromosome 22.

In approximately 10% of the patients, this deletion is inherited from a parent while in the other 90% cases it is acquired by mutation spontaneously. This microdeletion is detectable in 95% of patients with VFCS. 

Epidemiology

Velocardiofacial Syndrome is the most prevalent syndrome found associated with cleft palate. It is also the commonest syndrome caused by microdeletions and the second most prevalent syndrome found associated with congenital cardiac defects.

VCFS is seen in approximately 1 child out of 2,000 - 5,000 live births. However, there are varying statistics which vary according to the mode of data collection and method of verification of the diagnosis. In most studies, the reports of the diagnosis depended on birth records, neonatal examinations, or other unverified sources [7] [8].

There is a possibility of under-diagnosis of this condition since many features become apparent much later in life or even might go undetected. Severe complications include cardiac malformations which may occur in about 70% of VCFS cases.

Sex distribution
Age distribution

Pathophysiology

VCFS is caused by a microdeletion at the 11.2 band or locus of the short arm of chromosome 22. This in turn impairs the development and migration of neural crest cells, and development of the bronchial arches.

In about 90% of cases, the microdeletion is a new deletion occurring as a de-novo deletion or translocation involving 3-megabase in a region that contains at least 40 genes [9]. Because these genes are involved in the development of the heart and structures in the central nervous system, a number of coronary artery defects occur in this syndrome [10].

In the other 10% of cases, the mutation is inherited in an autosomal dominant pattern from a parent. Inheritance of this genetic mutation occurs in 50% of cases.

This genetic mutation is commonly associated with aortic arch, aortic branch, or pulmonary vessel defects, therefore, necessitating genetic testing in these patients [3]. However in this syndrome, there is a wide spectrum of features which may present in different combinations among patients, even of the same families [11] [12] [13].

Prevention

There is a 50% chance of transferring the mutated chromosome from a parent to an offspring. Therefore, genetic testing and counselling is recommended for parents with children with suspected or confirmed VFCS.

Antenatal ultrasonography may be necessary to determine the severity or complexity of VFCS in a fetus. Antenatal cardiac imaging of the fetus may also assist in determining the degree of cardiac malformation in the fetus. Most of the severe cardiac defects can be identified in fetus enabling appropriate decision by the doctor and parents about the continuation of pregnancy and treatment after birth.

Care should be taken in immunizing children with VFCS. Due to the possibility of immune compromise and lymphocyte dysfunction, such patients should not undergo immunization with live vaccines. To prevent secondary seizures, preoperative and postoperative serum calcium should be monitored in affected children.

All possible organs prone to defects in VFCS should be assessed and investigated for presence of abnormalities before any clinical procedure is undertaken to prevent secondary complications.

Summary

Velocardiofacial syndrome (VCFS) is a genetic disorder involving microdeletion of the 11.2 band of the short arm of chromosome 22. VCFS was first described by Shprintzen and his colleagues in 1978 [1].

The disorder presents with an array of congenital malformations affecting virtually every organ system in the body. It includes over 180 clinical features which may not be similar in all patients: typical abnormalities include cleft palate, cardiac defects, and a characteristic facies. Patients are often affected by speech defects, cognitive and developmental impairments, and psychiatric disorders [2].

Cardiac defects are found in approximately 75% of cases of VFCS and mainly involve the outflow portion of developing heart. The commonest cardiac defects in VFCS are interrupted aortic arch seen in up to 50% of cases, involvement of truncus arteriosus, and tetralogy of fallot. Other common defects include aortic stenosis and pulmonary artery abnormalities [3].

Immune defects found are secondary to thymic abnormality. The resulting immune deficiencies may worsen or improve over time [4] [5]. 

Eye deformities are also found in up to 70% of cases and are presented with cataracts and absence of the nasolacrimal ducts [6].

Diagnosis of VFCS involves genetic testing and investigations to determine the presence of major complications such as heart defects and immunosuppression.

Treatment of VFCS involves a multidisciplinary approach involving geneticists, genetic counsellors, pediatric cardiologists and cardiac surgeons, pediatric immunologists, plastic surgeons, and speech therapists.

Patient Information

Velocardiofacial syndrome (VCFS) is also known as digeorge syndrome or 22q11.2 syndrome. It is a genetic condition caused by a removal or deletion of a small part of chromosome 22. It presents with many malformations affecting virtually all the organs of the body.

There are 23 pairs of chromosomes in each cell of the body. In VFCS, there is a removal of a section of the short arm of the 22nd pair of chromosomes. This section contains genes which code for the formation of several structures including parts of the heart and contents of the head. Therefore this change (mutation) in the genes causes abnormalities in the body structures for which the absent genes are coded. In few cases, this genetic mutation is transferred from one parent to the offspring, although there is a 50% chance of that happening [16]. 

This syndrome is estimated to occur in one out of 2,000 to 5,000 births. This syndrome presents with a wide range of abnormalities. Whereas some of these abnormalities may occur from birth, others may not manifest till the child is older.

VFCS typically presents with abnormal shapes of structures in the face; with cleft palate, a term for incomplete fusion of the palate causing feeding problems. The syndrome is also associated with an abnormally small jaw, abnormal round shape of the tip of the nose, abnormal structure of the heart and blood vessels taking blood away from the heart.

The heart defects are particularly of concern because they may cause poor feeding, stunted growth, and poor mental abilities. Heart defects occur in every three out of four patients with VFCS. A few of the children with VFCS usually progress to developing serious psychiatric and personality disorders. Children with VFCS are also very prone to convulsions.

The eye may also be affected in patients with VFCS causing cataracts in both eyes and abnormalities in the blood vessels in the eye. Generally, affected children have speech problems, learning difficulties, behavioral abnormalities and also weak immune system.

This syndrome may be diagnosed by physical examination of the child. However, the diagnosis can be confirmed by using certain techniques to detect the genetic abnormalities within the cells. Other investigations to check for possible severe malformations such as heart defects are necessary one the diagnosis for VFCS is confirmed.

The treatment of this syndrome involves a team approach. Specialists from different medical fields - geneticists, genetic counsellors, heart surgeons, ear, nose and throat specialists, plastic surgeons, and physical and speech therapists - all work in concert for a very long duration for the treatment and management of the patient.

For the parents of any child in whom VFCS is suspected or has been confirmed, genetic counselling and testing is recommended to help in future pregnancies.

References

Article

  1. 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;15(1):56-62.
  2. 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; 34 (10):798-804.
  3. Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol. 1998; 32(2):492-8.
  4. 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; 136(3):409-18.
  5. Gennery AR. Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci. 2012; 69(1):17-27.
  6. Prabhakaran VC, Davis G, Wormald PJ, Selva D. Congenital absence of the nasolacrimal duct in velocardiofacial syndrome. J AAPOS. 2008;12(1):85-6
  7. Ryan AK, Goodship JA, Wilson DI, et al. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet; 1992;339:1138–1139.
  8. Óskarsdóttir 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.
  9. Shprintzen RJ. Velo-cardio-facial syndrome: 30 Years of study. Dev Disabil Res Rev. 2008;14(1):3-10.
  10. 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; 103(2):142-8.
  11. Cuneo BF. 22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes. Curr Opin Pediatr. 2001;13(5):465-72.
  12. McLean-Tooke A, Spickett GP, Gennery AR. Immunodeficiency and autoimmunity in 22q11.2 deletion syndrome. Scand J Immunol. 2007; 66(1):1-7.
  13. Leopold C, De Barros A, Cellier C, et al. Laryngeal abnormalities are frequent in the 22q11 deletion syndrome. Int J Pediatr Otorhinolaryngol. 2012; 76(1):36-40.
  14. Tarquinio DC, Jones MC, Jones KL, Bird LM. Growth charts for 22q11 deletion syndrome. Am J Med Genet A. 2012; 158 A (11):2672-81.
  15. 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. 
  16. McDonald-McGinn DM, Zackai EH. Genetic counseling for the 22q11.2 deletion. Dev Disabil Res Rev. 2008; 14(1):69-74. 

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Last updated: 2018-06-21 22:07