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%

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%

Others

Velopharyngeal insufficiency following adnoidectomy-64%

Isolated velopharyngeal insufficiency-37%

Neonatal hypocalcemia-74%

Schizophrenia-0.3-6.4%

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

Tbx-1

•          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

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

–        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

Autoimmunity

•          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?