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DiGeorge syndrome: still teaching us about the thymus

DiGeorge syndrome: still teaching us about the thymus. Kathleen Sullivan MD PhD. A word about nomenclature. Chromosome 22q11.2 deletion syndrome DiGeorge syndrome Velocardiofacial syndrome Conotruncal anomaly face Some CHARGE.

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DiGeorge syndrome: still teaching us about the thymus

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  1. DiGeorge syndrome:still teaching us about the thymus Kathleen Sullivan MD PhD

  2. 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.

  3. 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% The Phenotype of Chromosome 22q11.2 Deletion Syndrome

  4. 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%

  5. Where to look for the deletion? Velopharyngeal insufficiency following adnoidectomy 64% Isolated velopharyngeal insufficiency 37% Neonatal hypocalcemia 74% Schizophrenia 0.3-6.4%

  6. Any other clues? • Speech delay is almost universal if you do formal testing - 75% have obvious delay by the rapid Denver developmental exam • Dysmorphic facies

  7. The diagnosis is established by FISH

  8. 22 well-characterized genes

  9. The critical region was established by generating mice with comparable deletions

  10. The Heterozygous Murine Deletion Elizabeth A. Lindsay, Annalisa Botta, Vesna Jurecic, Sandra Carattini-Rivera, Yin-Chai Cheah, Howard M. Rosenblatt, Allan Bradley, Antonio Baldini Nature 401:379 (1999) Sandra Merscher, Birgit Funke, Jonathon Epstein, et al Cell 104:619 (2001) Loydie A. Jerome and Virginia Papaioannou Nature Genetics 27:286 (2001) 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

  11. 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

  12. TBX1 in humans Patients had classical features except not learning disability Yagi, H 2003 C isoform is most abundant

  13. More than TBX1? COMT, GPIBB may modify the phenotype Background genes outside the deleted region may modify the phenotype

  14. 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

  15. Behavior/School issues • 65.5% have a nonverbal learning disability • 25% have ADHD • 6-30% will develop schizophrenia

  16. 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 Immunodeficiency of Chromosome 22q11.2 Deletion Syndrome

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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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