Velocardiofacial Syndrome

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 survive 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 spectrum, 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.(B3)

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](B3)

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.(B3)

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](B3)

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](B3)

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 tumors with the 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.