What are the phenotypic characteristics of DiGeorge Syndrome (DGS) vs Velocardiofacial Syndrome (VCFS) vs Conotruncal Anomaly Face Syndrome (CAFS)?

DiGeorge, Velocardiofacial, and Conotruncal Anomaly Face Syndromes Are the Same Genetic Condition

DiGeorge Syndrome (DGS), Velocardiofacial Syndrome (VCFS), and Conotruncal Anomaly Face Syndrome (CAFS) all result from the same 22q11.2 microdeletion and represent phenotypic variability of a single genetic condition, not distinct disorders. 1, 2, 3

Unified Genetic Basis

• All three historically named syndromes are caused by partial deletion of the short arm of chromosome 22 at the q11.2 band 1
• The typical deletion spans 2.5 to 3 Mb from LCR22A to LCR22D on chromosome 22q11.2 2
• The large majority of affected individuals have identical 3 megabase deletions, while less than 10% have smaller deletions of 1.5 or 2.0 megabases 4
• Current nomenclature uses "22q11.2 deletion syndrome" to encompass all historical names (DiGeorge syndrome, Shprintzen syndrome, FACES, CATCH-22) 1, 2

Common Phenotypic Characteristics Across All Three Names

The following features occur across the phenotypic spectrum, regardless of which historical name was initially applied:

Craniofacial Features (93% of cases)

• Hypertelorism (widely spaced eyes) 1
• Saddle nose 1
• Shortened philtrum 1
• Low-set and abnormally shaped ears 1, 5
• Distinctive facial appearance that is part of the velocardiofacial spectrum 1

Cardiovascular Abnormalities (68% of cases)

• Conotruncal cardiac malformations are the primary cardiac manifestation 2, 5
• Cardiac outflow tract malformations 1
• Tetralogy of Fallot, interrupted aortic arch type B, and truncus arteriosus 6
• Congenital heart defects are the leading cause of mortality with 5-15% mortality rates, most deaths occurring in the first year of life 2

Immunological Abnormalities (64% thymic involvement)

• Thymic hypoplasia or aplasia 1, 5, 3
• T-cell lymphopenia affecting both CD4 and CD8 subsets 1
• Variable severity from complete athymia (CD3+ T lymphocytes <50 cells/μL) to partial thymic hypoplasia (CD3+ T lymphocytes <1500 cells/μL) 2, 7
• IgA deficiency and hypogammaglobulinemia occur in 2-13% of patients, with approximately 6% requiring IgG replacement 1, 7

Endocrine Abnormalities (63% of cases)

• Hypoparathyroidism with hypocalcemia 1, 2, 5, 3
• Hypoplasia of parathyroid glands 1

Palatal Abnormalities (48% of cases)

• Cleft palate 1, 3
• Velopharyngeal insufficiency 1, 3

Neurodevelopmental and Psychiatric Features (97% mental impairment)

• Mental impairment is the most common manifestation 3
• Neuropsychiatric disorders are the most common later-onset conditions and typically of greatest concern to families 2
• More than 180 clinical features have been described involving essentially every organ system 4
• Risk for severe psychiatric illness is 25 times higher than the general population, including attention deficit disorder, schizophrenia, and bipolar disorder 4

Clinical Variability and Diagnostic Implications

• The expression is highly variable with some individuals being essentially normal at the mildest end of the spectrum, and the most severe cases having life-threatening problems 4
• Significant inter- and intrafamilial clinical variability exists, consistent with a single gene or group of tightly linked genes as the common cause 3
• The historical use of different names (DiGeorge, velocardiofacial, conotruncal anomaly face) reflects diagnostic difficulties and the great variety of clinical presentations, not distinct genetic entities 5, 8

Inheritance Pattern

• 90-95% of cases are de novo deletions 2, 7
• 5-10% are inherited, with up to 25% of deletions being familial 2, 7, 3
• Affected individuals have 50% recurrence risk for offspring 2, 7