Epidemiology and Etiology
Epidemiology
- Incidence: 1 in 4,000–7,000 live births
- Most common human chromosomal deletion syndrome
- Growing prevalence due to the following factors:
- Surgical correction of cardiac defects improves the survival rate of affected patients, thus increasing their likelihood of passing on the condition.
- Parents who were previously unaware of their genetic condition are being diagnosed as genetic testing becomes more available.
- Earlier genetic techniques were not able to detect all deletions; newer technologies also cover atypical deletions.
Etiology
- Synonyms: velocardiofacial syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome (CTAF), Takao syndrome
- Caused by a heterozygous deletion of part of the long arm (q) of chromosome 22, region 1, band 1, sub-band 2 (22q11.2)
- The deletion of 22q11.2 is 10 times more common than the next most frequent deletion syndrome, suggesting that this region is inherently unstable.
- 93% of cases are de novo mutations during early fetal development.
- 7% of cases are inherited in autosomal dominant patterns from affected parents.
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Pathophysiology
- Approximately 30–50 genes are affected by the 22q11.2 deletion.
- Disrupts the development of the 3rd and 4th pharyngeal pouches
- Creates a defect in the embryonic development of the brain, neck, skeleton, and kidneys
- TBX1 is the main gene responsible for the DiGeorge phenotype. It plays a vital role in organ formation and regulation, affecting the formation of:
- Skull bones
- Mesenchyme of the face and palate
- Outflow tract of the heart
- Thymus and parathyroid stroma
- 22q11.2 deletions are associated with a higher risk of early onset Parkinson’s disease.
Clinical Presentation
DiGeorge syndrome has a marked variability in clinical expression among different individuals. Manifestations can include the following:
- Congenital cardiovascular disease:
- Interrupted aortic arch
- Patent truncus arteriosus
- Tetralogy of Fallot
- Atrial or ventricular septal defect
- Vascular rings (causing tracheal or esophageal compression)
- Abnormal craniofacial features:
- Hypertelorism, tubular nose, hooded eyes
- Cleft palate
- Low-set or posteriorly rotated ears
- Endocrine issues:
- Hypoparathyroidism (50% of cases; causes hypocalcemia, which can lead to seizures)
- Growth hormone deficiency
- Thymic aplasia/hypoplasia (leads to immunodeficiency due to reduced T cells):
- Complete DiGeorge syndrome:
- Only 1% of cases
- Thymus is completely absent
- Causes severe combined immunodeficiency (SCID); manifests as recurrent infections, chronic diarrhea, and failure to thrive
- Fatal unless promptly treated
- Partial DiGeorge syndrome:
- Range of normal to deficient T cell numbers
- Approximately 75% of patients with thymic defect
- Varying degree of immunodeficiency, although a normal number of T cells may be reached by adulthood (proliferation of existing T cells)
- Associated with humoral immunodeficiencies of immunoglobulin A (IgA) deficiency
- Complete DiGeorge syndrome:
- Neurological problems:
- Learning disabilities (up to 90% of cases), speech delay
- High risk of early onset Parkinson’s disease
- Conductive and sensorineural hearing loss
- Psychiatric disorders:
- Depression, bipolar disorder
- Attention deficit hyperactivity disorder (ADHD)
- Schizophrenia
- Miscellaneous: laryngotracheoesophageal defects, digestive motility issues, skeletal abnormalities, anomalies of the genitourinary and respiratory tract, autoimmune diseases such as Graves disease and rheumatoid arthritis
Facial appearance of a patient with atypical 22q11.2 deletion. Note the broad, square face; hypotelorism; narrow nasal base and broad nasal bridge; overhanging nasal tip; deviated nasal tip (state post cleft lip repair); short philtrum; narrow mouth; chin dimple; and broad neck.
Image: “Facial appearance of Patient VC901” by Elena Michaelovsky et al. License: CC BY 2.022q11.2 deletion features in a 48-year-old woman.
Image: “48-year-old woman with the 22q11.2 deletion” by Department of Psychiatry, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan. License: CC BY 2.0, edited by Lecturio.
(a) Cleft palate; had previous surgery
(b) Mild dysmorphic facial features, including a low anterior hairline, swollen eyelids, malar flatness, nose with a bulbous nasal tip, hypoplastic nasal alae and a square and flat nasal root, small mouth, and a thin upper lip
Mnemonic
DiGeorge syndrome signs can be summarized using the mnemonic CATCH-22:
- C: Congenital heart disease
- A: Abnormal facies
- T: Thymic aplasia
- C: Cleft palate
- H: Hypocalcemia/hypoparathyroidism
- 22: 22q11.2DS, found on chromosome 22
Diagnosis and Management
Diagnosis
Establishing a diagnosis is difficult due to the variability of phenotypes. Along with suggestive signs and symptoms, evaluation includes the following:
- Genetic testing—array comparative genomic hybridization (aCGH):
- Preferred test
- Detects deletions or duplications
- Lab work and imaging to identify associated defects:
- Cardiology:
- Electrocardiogram (ECG)
- Echocardiography
- Endocrine:
- Serum calcium and phosphorus levels (↓ PTH, ↓ calcium, ↑ phosphorus)
- Thyroid profile test
- Chest X-ray (to check absence of thymus)
- Immune function tests:
- CBC to evaluate for lymphopenia, immunoglobulin levels, T- and B-cell subsets
- Renal ultrasound (look for structural genitourinary tract abnormalities)
- Cardiology:
Management
Management is aimed at treating the associated features of the disease. Early intervention and developmental evaluation are key.
- Thymus transplantation or hematopoietic cell transplantation (HCT)
- Antibiotics (for treating frequent infections), IV immunoglobulins
- Cautionary use of blood transfusions and live attenuated vaccines
- Cardiac surgery to correct congenital heart abnormalities
- Lifelong vitamin D and calcium supplementation
Prognosis
There is no cure for DiGeorge syndrome. Life expectancy largely depends on the degree of cardiac defects (most important factor) and immunodeficiency.
- Complete DiGeorge syndrome:
- Without transplantation, the life expectancy of infants is < 1 year.
- In patients who undergo a transplant, most deaths occur in the first year post-transplant.
- Majority of deaths attributed to cardiac complications
- Partial DiGeorge syndrome: prognosis dependent on severity of cardiac defect, patient’s intellectual development, and follow-up care provided for their associated deficiencies