DiGeorge syndrome: Chromosome 22q11.2 deletion Kate Sullivan MD PhD The Children’s Hospital of Philadelphia Johnson City 2012
Download ReportTranscript DiGeorge syndrome: Chromosome 22q11.2 deletion Kate Sullivan MD PhD The Children’s Hospital of Philadelphia Johnson City 2012
DiGeorge syndrome: Chromosome 22q11.2 deletion Kate Sullivan MD PhD The Children’s Hospital of Philadelphia Johnson City 2012 Disclosure Statement of Financial Interest I, Kate Sullivan DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. A word about nomenclature Chromosome 22q11.2 deletion syndrome DiGeorge syndrome Clinical triad: cardiac, thymus, parathyroid Etiologies Velocardiofacial syndrome CH22q11.2 hemizygous deletion CHD7 mutations Maternal diabetes Maternal isotretinoin Chromosome 10 deletions Clinical triad Some CHARGE 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 Interrupted aortic arch B Pulmonary atresia Aberrant subclavian Tetralogy of Fallot 1.1% 50-60% 33-45% 25% 11-17% Where to look for the deletion? Velopharyngeal insufficiency following adnoidectomy 64% Isolated velopharyngeal insufficiency 37% Neonatal hypocalcemia 74% Schizophrenia 0.3-6.4% Any other clues? Speech delay Almost universal if you do formal testing 75% fail the rapid Denver speech criteria Dysmorphic facies Notice preauricular pit Father/Daughter Posteriorly rotated ears Simple helices Many other features The diagnosis is established by FISH, multiplex ligation-dependent probe amplification (MLPA), or SNP array The deletion has many genes Tbx-1 Expressed in developing mesenchyme Expressed in pharyngeal arches, otic vesicle Part of a cascade of transcription factors Parathyroid Thymus Anterior heart field TBX1 mutations in humans look like Ch22qD Yagi, H 2003 The significance of 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 psychiatric diseases Obviously not all patients are the same… The Immunodeficiency 60-77% of patients have quantitative T cell defects Only ≈0.2% have absent T cells 2-4% IgA deficiency 6% Hypogammaglobulinemia The Role of the Thymus 15-20% of patients have an absent anatomic thymus Thymic tissue is found in aberrant locations Only ≈0.2% of patients have no T cells and truly have thymic aplasia Hypoplasia Restricts T cell output Movies courtesy of Richard Lewis, Stanford Early thymic development Human=6wk Ectoderm Endoderm Thymic tissue is derived from pharyngeal pouch endoderm Hollander Imm Rev 209:28 Clinical Immunodeficiency 7% of all ages have significant, serious infections 9% of kids have autoimmune disease (may be ≈25% in adults- Bassett 2005) Older children continue to get infections 27% recurrent sinusitis 25% recurrent otitis media 7% recurrent bronchitis 4% recurrent pneumonia Sullivan J. Ped. 2001 P=0.0006 P=0.05 Staple Ped All Imm 2005 Autoimmunity Juvenile arthritis 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 6% ITP 20% Thyroid disease CD3 T cells Homeostatic proliferation Thymus 2 cells exported Thymus Peripheral proliferation 10 cells total Only two T cell receptors 10 cells exported Ten different T cell receptors Evidence of homeostatic expansion Adult Controls Adult Patients P value Oligoclonal 1.55 8.6 0.0001 Absent 1.44 7.1 0.0009 TREC circles Piliero Blood 2004 Zemble Clin Imm 2010 T cells default to Th2 with homeostatic expansion P=0.07 P=0.0014 Zemble Clin Imm 2010 T cell summary Quantitative defects most apparent in infancy T cell numbers normalize with age Qualitative T cell defects accrue with age Repertoire degradation Poor proliferation Th2 skewing ??? Poor support for B cell development/differentiation B cells P=0.01 P=0.02 P=0.001 Immunoglobulin Levels: ESID, USIDNET, LASID collaboration IgG vs Age 3000 IgG mg/dl 2500 2000 1500 1000 500 0 0 10 20 30 40 50 Age (y) IgM vs Age IgA vs Age 500 1000 400 IgM mg/dl IgA mg/dl 800 600 400 300 200 100 200 0 0 0 10 20 30 Age (y) 40 50 0 10 20 30 Age (y) 40 50 What to do? Prophylactic antibiotics Immunoglobulin replacement Thymus transplant Peripheral blood T cells Thymus enhancement Thymus transplants Surgical thymectomy specimens Screened for infection Not HLA matched 0.5mm thick slices of 15mm X 15mm Cultured for 12-21d to remove donor T cells Implanted into the quadriceps >70% survival (n=60) Markert Clin Imm 135:236 T cell recovery is adequate but not robust B cell function Normal immunoglobulin levels 100% normal IgG 91% normal IgA 77% normal IgM 100% normal tetanus titers Markert Clin Imm 135:236 Can thymic function be enhanced? Fibroblast growth factor 7-TEC expansion Estrogen-expands thymic tissue Summary Developmental delay/Behavioral problems are the biggest long term challenges Cardiac anomalies Most common cause of death Monitor calcium carefully The immune deficiency ranges from none to profound Most kids have recurrent sinopulmonary infections Prophylactic antibiotics Immunoglobulin for hypogammaglobulinemia Rarely, thymus transplants are required Thank you!