What is Velocardiofacial (22q11.2 deletion) syndrome?

What is Velocardiofacial Syndrome (22q11.2 Deletion Syndrome)?

Velocardiofacial syndrome (VCFS), DiGeorge syndrome, and conotruncal anomaly face syndrome are all names for the same genetic condition—22q11.2 deletion syndrome—which represents phenotypic variability of a single microdeletion on chromosome 22. 1

Genetic Basis

• 22q11.2 deletion syndrome is the most common microdeletion syndrome in humans, affecting approximately 1 in 2,000 to 1 in 3,000 live births. 2, 1
• The typical deletion spans 2.5 to 3 megabases from LCR22A to LCR22D on chromosome 22q11.2, encompassing approximately 40 genes. 1, 3
• 90-95% of cases are de novo deletions, while 5-10% are inherited from an affected parent. 1, 4
• Affected individuals have a 50% recurrence risk for offspring. 1, 4
• The TBX1 gene within this region is the most widely studied gene associated with the cardiac manifestations. 1, 5

Clinical Manifestations

Cardiac Features

• Congenital heart defects occur in 68% of patients and represent the leading cause of mortality. 1
• Conotruncal cardiac anomalies (tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, ventricular septal defects) are the primary cardiac manifestations. 1, 5
• Mortality rates range from 5-15%, with most deaths occurring in the first year of life related to complex congenital heart disease. 1, 5
• Children with 22q11.2DS and congenital heart defects have higher mortality than children with comparable heart defects without the deletion. 5

Immunological Features

• Thymic hypoplasia or aplasia leads to variable T-cell immunodeficiency. 1, 4
• Complete athymia is defined by CD3+ T lymphocytes <50 cells/μL and requires thymus transplantation for T-cell reconstitution. 1, 4
• Partial thymic hypoplasia (CD3+ T lymphocytes <1500 cells/μL) typically improves over time with periodic re-evaluation. 1, 4
• Patients are at risk for opportunistic infections including Pneumocystis jirovecii pneumonia, CMV pneumonitis, and persistent candidiasis. 1, 4
• Live vaccines should not be administered without documented normal T-cell responses to mitogens and antigens. 1, 4

Endocrine Features

• Hypoparathyroidism with hypocalcemia occurs in 63% of patients. 1
• Regular calcium monitoring is essential, particularly during stress, illness, or surgery. 1, 4
• Prompt treatment with calcium and vitamin D supplementation is required for hypocalcemia. 1, 4

Neuropsychiatric and Developmental Features

• Mental impairment and developmental delay are common manifestations. 1, 3
• Neuropsychiatric disorders are the most common later-onset conditions and typically of greatest concern to families. 1
• The risk for severe psychiatric illness (including schizophrenia, bipolar disorder, and attention deficit disorder) is 25 times higher than the general population. 3
• Psychiatric conditions may emerge in adolescence and adulthood, requiring lifelong monitoring. 1, 3

Additional Features

• Palatal abnormalities including cleft palate and velopharyngeal insufficiency affecting speech. 3, 6
• Facial dysmorphism (though often subtle). 4, 7
• Renal anomalies, skeletal defects, and eye anomalies. 7, 8
• The syndrome has an expansive phenotype with more than 180 clinical features described involving essentially every organ system. 3

Phenotypic Variability

• Expression is highly variable, with some individuals being essentially normal at the mildest end of the spectrum, while the most severe cases have life-threatening problems. 3
• Each patient requires tailored care based on their specific manifestations. 1, 6

Diagnosis

• Initially a clinical diagnosis based on constellation of features. 3
• Today diagnosed with extremely high accuracy by fluorescence in situ hybridization (FISH) and other laboratory techniques detecting the 22q11.2 deletion. 3
• Chromosome 22q11.2 deletions are absent in large populations of healthy controls, implying high collective penetrance for at least one major phenotypic feature. 2

Age-Dependent Management Priorities

• Infancy and preschool years: Focus on acute medical problems including congenital heart disease, immune disorders, feeding problems, cleft palate, and developmental delays. 3
• School years: Management shifts to cognitive, behavioral, and learning disorders. 3
• Late adolescence and adulthood: Focus on potential psychiatric disorders including psychosis, along with ongoing medical surveillance. 2, 3

Essential Multidisciplinary Care Requirements

• Immunology for immune deficiency management and infection prevention strategies. 1, 4
• Cardiology for congenital heart defects and preconception counseling. 1, 5
• Endocrinology for hypoparathyroidism management. 1, 4
• Developmental pediatrics for cognitive and behavioral issues. 1, 4
• Genetics for ongoing counseling regarding 50% recurrence risk. 1, 4
• Psychiatry for monitoring and managing neuropsychiatric conditions. 1, 3
• Additional specialists (ENT, nephrology, ophthalmology) based on individual manifestations. 1