Rabu, 07 September 2011

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%
        Truncus arteriosus-8%
          Palatal anomaly-69-100%
          Speech delay-75%
          Renal anomaly-36-37%
          Skeletal anomaly-17-19%

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%

The diagnosis is established by FISH

22 well-characterized genes
The critical region was established by generating mice with comparable deletions 

The Heterozygous  Murine  Deletion
25-50% of mice have cardiovascular anomalies
o   Aberrant great vessels (right subclavian, IAAB)
o   VSDs
o   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

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
        79% significant motor delay
        53% significant expressive delay
        26% significant receptive delay

        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

        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?

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