General Medicine

DiGeorge Syndrome PDF

DiGeorge Syndrome Lecture Note

A word about nomenclature

•          Chromosome 22q11.2 deletion syndrome
•          DiGeorge syndrome
•          Velocardiofacial syndrome
•          Conotruncal anomaly face
•          Some CHARGE

The majority of patients with DiGeorge syndrome, VCFS, CTAF have hemizygous deletions of chromosome 22q11.2.  The nomenclature is not synonymous.

The Phenotype of Chromosome 22q11.2 Deletion Syndrome

  • Cardiac anomaly 75%
    • TOF-20%
    • IAA-15%
    • Truncus arteriosus-8%
  • Palatal anomaly-69-100%
  • Hypocalcemia-17-60%
  • Speech delay-75%
  • Renal anomaly-36-37%
  • Skeletal anomaly-17-19%
  • Immunodeficiency-60-77%

DiGeorge Syndrome

Where to look for the deletion?

Cardiac Diseases
  • Any cardiac lesion-1.1%
  • Interrupted aortic arch-50-60%
  • Pulmonary atresia-33-45%
  • Aberrant subclavian-25%
  • Tetralogy of Fallot-11-17%
  • Velopharyngeal insufficiency following adnoidectomy-64%
  • Isolated velopharyngeal insufficiency-37%
  • Neonatal hypocalcemia-74%
  • Schizophrenia-0.3-6.4%

The diagnosis is established by FISH

DiGeorge Syndrome

22 well-characterized genes

DiGeorge Syndrome

The critical region was established by generating mice with comparable deletions

DiGeorge Syndrome

The Heterozygous  Murine  Deletion

  • 25-50% of mice have cardiovascular anomalies
    • Aberrant great vessels (right subclavian, IAAB)
    • VSDs
    • Conotruncal anomalies rare
  • Thymus was variably effected depending on background strain
  • Parathyroid gland variable
  • Homozygous mice have additional features of Ch22q11.2 D


•          Expressed in developing mesenchyme
•          Expressed in pharyngeal arches, otic vesicle, tooth buds, sclerotome
•          Heterozygous mutations of Tbx-1 are associated with great vessel defects in mice
•      Homozygous deficient mice have a small mandible, low set ears, a single cardiac outflow tract, deficient thymus/parathyroid/salivary glands

TBX1 in humans

DiGeorge Syndrome

More than TBX1?

•          COMT, GPIBB may modify the phenotype
•          Background genes outside the deleted region may modify the phenotype

The significance of establishing the diagnosis

  • Toddlers
    –        79% significant motor delay
    –        53% significant expressive delay
    –        26% significant receptive delay
  • School-age
    –        12.7% average IQ (Weschler)
    –        25.5% low average
    –        34.5% borderline
    –        27.3% retarded
  • Behavior/School issues
    •          65.5% have a nonverbal learning disability
    •          25% have ADHD
    •          6-30% will develop schizophrenia

The Immunodeficiency of Chromosome 22q11.2 Deletion Syndrome

•          60-77% of patients have laboratory evidence of quantitative T cell defects
•          Only 0.5-1.0% have absent T cells
•          T cell proliferation is usually normal
•          2-4% are IgA deficient
•          10% have delayed production of IgG

The Role of the Thymus in the Immunodeficiency

DiGeorge Syndrome

–        15-20% of patients have an absent anatomic thymus
–        Thymic tissue is found in aberrant locations
–        Only 0.5-1.0% of patients have no T cells and truly  have thymic aplasia

80% of patients have thymic hypoplasia

•          Restricts T cell output
•          T cells are qualitatively normal
•          CD4/CD25 T cells are markedly decreased
•          There can be secondary effects on antibody production

Clinical Immunodeficiency

  • 7% of all ages have significant, serious infections
  • 9% have autoimmune disease
  • Older children and adults continue to get infections
    27% recurrent sinusitis
    25% recurrent otitis media
    7% recurrent bronchitis
    4% recurrent pneumonia


•          JRA is seen 20X more frequently  (2%)
•          ITP is seen 200X more frequently  (4%)
•          AHA, IBD are seen in about 1%
•          Older patients develop autoimmune diseases of adults

T cell findings

•          The mean T cell number is about 50% of normal in infancy
•          The mean T cell number is about 80% of normal in adulthood
•          Why are the adults sick so much?