Velocardiofacial Syndrome

Article Author:
Bradie Bishop
Article Author:
Rebecca Ward
Article Editor:
Robert Brady
Updated:
8/16/2020 3:06:44 AM
PubMed Link:
Velocardiofacial Syndrome

Introduction

Initially described in the 1960s by Dr. Angelo Di George [1], velocardial facial syndrome (otherwise known as Di George syndrome or Chromosome 22q11.2 syndrome) is the most common microdeletion syndrome in humans. [2][3] A 3 Mb deletion of LCR22A-D is the most common deletion present, though other deletions can be seen, with varying phenotypes. [3] Though there are a variety of presentations and phenotypes possible in velocardial facial syndrome, common presenting features include immune deficiency, recurrent infections, hypocalcemia, seizures, CNS anomalies, psychiatric problems, short stature, macro- or microcephaly, intellectual delays, congenital heart disease genitourinary anomalies, and palatal anomalies. [3] Symptoms and phenotype can range from only a few features to severe and life-threatening. A long narrow face with a tubular nose, thin palpebral fissures, and a small mouth are present in greater than 90% of cases. [4]

Etiology

Velocardial facial syndrome is the result of a microdeletion of DNA on a single copy of chromosome 22q11.2. [5] Most deletions occur spontaneously. However, as patients with velocardial facial syndrome are surviving into adulthood, their potential offspring have a 50% chance of inheriting the syndrome. [3] A variety of breakpoints can occur, with variability in phenotypes secondary to where and what DNA is lost. Deletions are categorized as proximal, central, and distal. [3]

The actual break in the chromosome occurs during an unequal meiotic exchange. An area of the chromosome with low copy number repeats is particularly susceptible to loss during meiosis. [6] Approximately 30 to 40 genes can be lost. Most patients with velocardial facial syndrome have 3 million base pairs deleted. 

Without the 22q11.2 region, abnormal neural crest migration occurs, resulting in the 3rd and 4th pharyngeal pouches improperly migrating. Subsequent thymic hypoplasia, parathyroid hypoplasia, and conotruncal cardiac anomalies occur and lead to immunodeficiency and hypocalcemia. A gene known as T-box transcription factor (TBX1) is thought to be responsible for some of the abnormal neural crest migration. [7]

Epidemiology

Most patients with velocardial facial syndrome arise from a de novo microdeletion, with subsequent autosomal dominant inheritance. Prevalence ranges from 1 to 2 per 4,000 live births, with an increased incidence in patients with cardiovascular malformations. [3][8][7] There is no male or female predominance. [9]

There does not appear to be an association with any ethnic group and the development of velocardial facial syndrome. [7]

Though patients with velocardial facial syndrome generally have unaffected fertility, their offspring have a 50% chance of inheriting the syndrome. [5]

Pathophysiology

Velocardial facial syndrome has a wide range of findings due to both differences in the amount of genetic material lost and environmental factors. The most common results are developmental delays, cardiac anomalies, palatal anomalies, and immune deficiency. [6][9]

History and Physical

Major birth defects like conotruncal cardiac anomalies, thymic hypoplasia, or velopharyngeal insufficiency, should prompt consideration of velocardial facial syndrome in a newborn infant, particularly if the patient also has hypocalcemia. [5] Other patients may be picked up when a newborn is screened for severe combined immunodeficiency. [7]

Psychiatric symptoms, such as difficulties in learning or attention deficit disorder may be the presenting complaints of patients with velocardial facial syndrome, particularly in older adolescents and adults. [5] Up to a quarter of patients will develop schizophrenia or schizoaffective disorder.[5]

The four features most commonly are developmental delays, cardiac anomalies, palatal anomalies, and immune deficiency. [6] [9]

Features of a velocardial facial syndrome: [5][6]

  • Dysmorphic facial features: long narrow face, tubular nose with a bulbous tip, narrow palpebral fissures, small mouth, and ears
  • Development and learning disabilities, particularly in math
  • Hypernasal speech
  • Hypocalcemia and hypoparathyroidism
  • Hypo- or hyperthyroidism
  • Psychiatric disorders, including schizophrenia, depression, autism, attention-deficit, obsessive-compulsive
  • Recurrent seizures
  • Cardiovascular malformations
  • Scoliosis
  • Renal and urogenital anomalies
  • Strabismus
  • Recurrent infections
  • Obesity

Evaluation

Multiplex ligation-dependent probe amplification (MLPA) and single nucleotide polymorphism (SNP) arrays are the preferred methods to detect microdeletions of chromosome 22q11, but fluorescence in-situ hybridization can be used as well. [7] Pre-natal ultrasonography can detect clinical features, such as an interrupted aortic arch, that should prompt consideration of velocardial facial syndrome. [6] In particular, one study recommended that finding polyhydramnios in conjunction with another low-risk anomaly should prompt genetic testing. [6]

Hypocalcemia is a common finding and requires close monitoring. [5]

Thrombocytopenia with increased platelet size can be seen in patients with velocardial facial syndrome when the GPIBB gene is deleted, resulting in decreased expression of GPIb-IX-V on the platelet surface. [10] [6] An increased propensity for bleeding and epistaxis is frequently seen in patients with this deletion. [10]

As patients age, hypothyroidism and hypoparathyroidism often develop. [5]

Treatment / Management

Four features commonly seen in patients with velocardial facial syndrome that significantly impact the quality of life and require medical management are developmental delays, cardiac anomalies, palatal anomalies, and immune deficiency. [6] Patients should be seen with a multi-disciplinary team based on their particular phenotype and their age.

The cardiac anomalies most commonly seen with velocardial facial syndrome are tetralogy of Fallot, pulmonary atresia, truncus arteriosus, interrupted aortic arch, and ventricular septal defect. Early intervention by an experienced pediatric cardiothoracic surgeon is ideal for possible repair and or monitoring. Cardiac abnormalities have the most significant impact on morbidity and mortality. [6]

Palatal defects can cause difficulties in feeding due to muscle weakness in the nasopharyngeal area. [6] Nasogastric or gastrostomy feeding tubes may be necessary to aid in feeding; however, many feeding difficulties can be managed with thickeners and anti-reflux medications. [6] Breastfeeding may be extremely challenging due to muscle weakness and cleft palate. Discussing options and expectations with new parents should be considered a critical part of the care plan.

Patients with hypocalcemia should be supplemented with calcium and vitamin D, and their levels monitored. Hypercalcemia can be very damaging and should be avoided.[6]

As a patient with velocardial facial syndrome ages, his medical needs will change, and things like early education of parents are key. Additionally, growth should be evaluated using specialized growth charts. [9]

Differential Diagnosis

Thymic aplasia and congenital hypoparathyroidism can be seen in:[7]

  • CHARGE syndrome
  • Chromosome anomalies on 4q21.3, 10p13-14, 11q23-ter
  • Maternal diabetes or retinoic acid exposure

Other syndromes that may be considered include Smith-Lemli-Opitz syndrome, Kabuki syndrome, and Goldenhar syndrome. [6]

Due to the subtle and varied phenotype of velocardial facial syndrome, it is important to keep it on the differential diagnosis in any patient with congenital anomalies, learning difficulties, and immune deficiencies.

Prognosis

Complications of congenital cardiac anomalies can result in childhood death (less than 4%), but with increasing knowledge of how to repair these anomalies, many patients are living into adulthood. There has been no defined life expectancy for these patients. [6]

Complications

Cardiac anomalies are commonly seen in velocardial facial syndrome and frequently need repair. Complications from surgery, particularly in the newborn stage, may occur and should be explored with parents before surgery.

Autoimmune disease is seen in approximately 10% of patients with velocardial facial syndrome, most likely secondary to their immune deficiency from thymic hypoplasia. [6] Additionally, these patients appear to have an increased incidence of allergies as well. [6]

Idiopathic thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) occur with increased frequency in patients with velocardial facial syndrome. [10]

Velocardial facial syndrome patients are at increased risk for hematologic malignancies due to a depressed immune system. [10] Recent studies have demonstrated an association of atypical teratoid/rhabdoid tumor with SMARCB1 variant with velocardial facial syndrome.

Depending on the severity of immunodeficiency, patients with velocardial facial syndrome may be at higher risk for viral infections, particularly in childhood. These infections may last longer and have more frequent bacterial infections superimposed. Close monitoring and early treatment are required.

Deterrence and Patient Education

Learning disabilities are a common feature of velocardial facial syndrome and children may benefit from early intervention. Parents should be educated about milestones to look for and warning signs to help their child seek intervention as soon as possible. 

Moving into adolescence and adulthood, the signs and symptoms of schizophrenia, depression, and attention deficit disorder, among other psychiatric illness, should be discussed as they are common findings associated with velocardial facial syndrome.

No environmental or age-related factors have been implicated in the deletion of chromosome 22q11.

Pearls and Other Issues

Catch-22 is a common pneumonic used to remember the most common phenotypes in patients with velocardial facial syndrome. The 22 refers to the chromosome.

  • C - cardiac anomalies
  • A - abnormal facies
  • T - thymic hypoplasia
  • C - Cellular immune deficiency
  • H - hypoparathyroidism and hypocalcemia

Enhancing Healthcare Team Outcomes

Velocardial facial syndrome requires an interprofessional team approach to take care of the patient. The syndrome has features that span many fields, including medical genetics, pediatrics, psychiatry, endocrinology, speech pathology, neurology, orthopedics, ophthalmology, family medicine, cardiovascular surgery, gastroenterology, and immunology.

The expectations for each stage of development should be discussed early on with parents, with a particular emphasis on their specific child's phenotype. Even within families, the presenting symptoms can range wildly, so care should ideally be tailored to the individual patient.


References

[1] Di George AM,Lischner HW,Dacou C,Arey JB, Absence of the thymus. Lancet (London, England). 1967 Jun 24;     [PubMed PMID: 4165192]
[2] Sullivan KE, Chromosome 22q11.2 deletion syndrome and DiGeorge syndrome. Immunological reviews. 2019 Jan;     [PubMed PMID: 30565249]
[3] Burnside RD, 22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features. Cytogenetic and genome research. 2015;     [PubMed PMID: 26278718]
[4] Adams DJ,Clark DA, Common genetic and epigenetic syndromes. Pediatric clinics of North America. 2015 Apr;     [PubMed PMID: 25836705]
[5] Kapadia RK,Bassett AS, Recognizing a common genetic syndrome: 22q11.2 deletion syndrome. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2008 Feb 12;     [PubMed PMID: 18268261]
[6] McDonald-McGinn DM,Sullivan KE, Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine. 2011 Jan;     [PubMed PMID: 21200182]
[7] Swillen A,McDonald-McGinn D, Developmental trajectories in 22q11.2 deletion. American journal of medical genetics. Part C, Seminars in medical genetics. 2015 Jun;     [PubMed PMID: 25989227]
[8] Panamonta V,Wichajarn K,Chaikitpinyo A,Panamonta M,Pradubwong S,Chowchuen B, Birth Prevalence of Chromosome 22q11.2 Deletion Syndrome: A Systematic Review of Population-Based Studies. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2016 Aug;     [PubMed PMID: 29906080]
[9] Hacıhamdioğlu B,Hacıhamdioğlu D,Delil K, 22q11 deletion syndrome: current perspective. The application of clinical genetics. 2015;     [PubMed PMID: 26056486]
[10] Lambert MP,Arulselvan A,Schott A,Markham SJ,Crowley TB,Zackai EH,McDonald-McGinn DM, The 22q11.2 deletion syndrome: Cancer predisposition, platelet abnormalities and cytopenias. American journal of medical genetics. Part A. 2018 Oct;     [PubMed PMID: 28940864]