DiGeorge Syndrome

DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). Conotruncal anomalies present as congenital heart defects. Other manifestations consist of characteristic facial features, frequent infections, and neuropsychiatric disorders.
Diagnosis is obtained by a combination of clinical findings, laboratory tests (reduced T cells and low calcium), echocardiogram, and genetic analysis. Treatment can include calcium supplementation, prophylactic antibiotics, surgery (for heart defects and palate abnormalities), and thymus or hematopoietic cell transplantation. Prognosis depends on the severity of cardiac anomaly and immunodeficiency.

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Epidemiology and Etiology

Epidemiology

  • Incidence: 1 in 4,0007,000 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.
Autosomal dominant

Diagram of the inheritance pattern of autosomal dominant conditions

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Pathophysiology

  • Approximately 3050 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.
Digeorge syndrome genetics

DiGeorge syndrome: deletion at 11.2 of q arm

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Digeorge syndrome genetics and presentation

Pathophysiology of DiGeorge syndrome

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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
  • 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

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)

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

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