Immunologic Features 22q11.2DS. Chiraag S. Patel, MD
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1 Immunologic Features 22q11.2DS Chiraag S. Patel, MD
2 Objectives Genetics and DiGeorge Syndrome Thymus Immune cells (T-, B-, and NK cells) 22q11.2DS-associated disorders autoimmune and allergic diseases Treatment Vaccines References
3 Genetics of 22q11.2 deletion syndromes DiGeorge syndrome (DGS) >90% associated with chromosome 22q11.2 deletion lesser associated with 10p14 deletion, chromodomain helicase DNA binding protein (CHD7), prenatal exposure to isotretinoin,?high glucose Velocardiofacial syndrome % have 22q11.2 deletion Immune deficiency is a part of DGS and not correlated with degree of other phenotypic features
4 DiGeorge Syndrome Cardiac anomalies Immunodeficiency Hypocalcemia from parathyroid gland hypoplasia Nomenclature The term 22q11.2 deletion syndrome is used to refer to patients who have the deletion and DiGeorge Syndrome (DGS) is used when relying on clinical features
5 Thymus Thymic hypoplasia partial DGS decreased T cells 75-80% of infants Thymic aplasia complete DGS absence of T cells corresponding humoral defects low antibodies 1% of infants Normal T-cell counts in 20% of patients Thymus size not predictive of T-cell counts
6 T-cells T-cell numbers range from none (complete DGS) to normal (partial DGS) Improves first year of life homeostatic expansion vs generation of new cells rate of decline is slower than controls Reduced T-cell receptor repertoire 22q11.2DS patients with a defect in IL-7Ra IL-7 signaling is crucial for survival, expansion, and homeostasis of naïve CD4+ T-cells
7 B-cells and NK cells B-cells usually intact 22q11.2 deletion associated with increase of: IgA deficiency Specific Antibody Deficiency Recent studies suggest functional NK (natural killer) cell defects in pdgs Cutaneous viral (e.g. warts and molluscum)
8 Infections Most common: recurrent otitis media (ear infections) monitor for hearing loss Palatal dysfunction ability to close of nasopharynx recurrent sinusitis Also with recurrent bronchitis and pneumonia Fungal, Pnuemocystis, and viral infections in complete DiGeorge Syndrome (DGS)
9 Autoimmune Disorders Affects 10-23% of patients with 22q11DS Mechanism: Reduction of Treg (CD4 + CD25 + cells) Compensatory expansion of T-cells Children Juvenile rheumatoid arthritis Immune thrombocytopenia Autoimmune hemolytic anemia Inflammatory Bowel Disease (e.g. Celiac disease) Adults Psoriasis Vitiligo Rheumatoid arthritis Immune thrombocytopenia
10 Atopic Disease Increased prevalence of atopy (Th2 skewing) in partial DGS Environmental allergies ( hayfever ) Atopic dermatitis (eczema) Asthma
11 Treatment Humoral (B-cell) defects antibodies immunoglobulin replacement therapy Cellular (T-cell) defects thymus transplantation peripheral T-cell transplantation (fully matched) antibiotic prophylaxis antifungal, antiviral, antipneumocystis Blood products: CMV-negative and irradiated Thymus-sparing cardiac surgery
12 Vaccines No live vaccines without T-cell phenotyping yellow fever, varicella-zoster, MMR, rotavirus, nasal influenza (injectable influenza is fine) Only give live vaccinations if: CD4 + cells >400 cells/mm 3 (= CD8+ >200 cells/mm 3 ) Adequate mitogen proliferation of T-cells Delay or holding vaccines have resulted in infections 63% of unvaccinated children were infected with varicella (chicken pox)
13 References I Azzari C, Gambineri E, Resti M, et al. Safety and immunogenicity of measles-mumps-rubella vaccine in children with congenital immunodeficiency (DiGeorge syndrome). Vaccine 2005; 23: Chinen J, Rosenblatt HM, Smith EO, Shearer WT, Noroski LM. Long-term assessment of T-cell populations in DiGeorge syndrome. J All Clin Immunol 2003; 111: Cirillo, E., Giardino, G., Gallo, V., D'Assante, R., Grasso, F., Romano, R., et al. (2015). Severe combined immunodeficiency-an update. Annals of the New York Academy of Sciences, n/a n/a. DiGeorge AM. Discussions on a new concept of the cellular basis of immunology. J Pediatr 1965; 67: 907. Di Cesare, S., Puliafito, P., Ariganello, P., Marcovecchio, G. E., Mandolesi, M., Capolino, R., et al. (2015). Autoimmunity and regulatory t cells in 22q11.2 deletion syndrome patients. Pediatric Allergy and Immunology : Official Publication of the European Society of Pediatric Allergy and Immunology, n/a n/a. Hacıhamdioğlu, B., Hacıhamdioğlu, D., & Delil, K. (2015). 22q11 deletion syndrome: current perspective. The Application of Clinical Genetics, 8, Hofstetter, A. M., Jakob, K., Klein, N. P., Dekker, C. L., Edwards, K. M., Halsey, N. A., et al. (2014). Live vaccine use and safety in DiGeorge syndrome. Pediatrics, 133(4), e Jawad AF, McDonald-McGinn DM, Zackai E, Sullivan KE. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr 2001; 139: Kobrynski, L. J., & Sullivan, K. E. (2007). Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. The Lancet, 370(9596), Maggadottir, S. M., & Sullivan, K. E. (2013). The diverse clinical features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). The Journal of Allergy and Clinical Immunology. in Practice, 1(6),
14 References II Markert ML, Sarzotti M, Ozaki DA, et al. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood 2003; 102: Moylett EH, Wasan AN, Noroski LM, Shearer WT. Live viral vaccines in patients with partial DiGeorge syndrome: clinical experience and cellular immunity. Clin Immunol 2004; 112: O. Bartsch, M. Nemeckova, E. Kocarek, A. Wagner, A. Puchmajerova, M. Poppe, K. Ounap, P. Goetz, DiGeorge/ velocardiofacial syndrome: FISH studies of chromosomes 22q11 and 10p14, and clinical reports on the proximal 22q11 deletion, Am. J. Med. Genet. 117A (2003) 1 5. Perez, E. E., Bokszczanin, A., McDonald-McGinn, D., Zackai, E. H., & Sullivan, K. E. (2003). Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Pediatrics, 112(4), e325. Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 1997; 34: Staple, L., Andrews, T., McDonald-McGinn, D., Zackai, E., & Sullivan, K. E. (2005). Allergies in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) and patients with chronic granulomatous disease. Pediatric Allergy and Immunology : Official Publication of the European Society of Pediatric Allergy and Immunology, 16(3), Sullivan, K. (2004). Live viral vaccines in patients with DiGeorge syndrome. Clinical Immunology, 113(1), /j.clim Sullivan KE, McDonald-McGinn D, Driscoll D, Emanuel BS, Zackai EH, Jawad AF. Longitudinal analysis of lymphocyte function and numbers in the first year of life in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/ velocardiofacial syndrome). Clin Labor Diag Immunol 1999; 6: Zheng, P., Noroski, L. M., Hanson, I. C., Chen, Y., Lee, M. E., Huang, Y., et al. (2015). Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome. The Journal of Allergy and Clinical Immunology, 135(5),
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