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Immunologic Features 22q11.2DS
Chiraag S. Patel, MD
Objectives � Genetics and DiGeorge Syndrome
� Thymus
� Immune cells (T-, B-, and NK cells)
� 22q11.2DS-associated disorders � autoimmune and allergic diseases
� Treatment
� Vaccines
� References
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 � 80-100% have 22q11.2 deletion
� Immune deficiency is a part of DGS and not correlated with degree of other phenotypic features
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
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
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
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)
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)
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
Atopic Disease � Increased prevalence of atopy (Th2 skewing) in
partial DGS
� Environmental allergies (“hayfever”)
� Atopic dermatitis (eczema)
� Asthma
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
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/mm3 (= CD8+ >200 cells/mm3) � Adequate mitogen proliferation of T-cells
� Delay or holding vaccines have resulted in infections � 63% of unvaccinated children were infected with
varicella (chicken pox)
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: 1668–71.
� 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: 573–79.
� 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, 123–132.
� 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), e946–54.
� 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: 715–23.
� Kobrynski, L. J., & Sullivan, K. E. (2007). Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. The Lancet, 370(9596), 1443–1452.
� 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), 589–594.
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: 1121–30.
� 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: 106–12.
� 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: 798–804.
� 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), 226–230.
� Sullivan, K. (2004). Live viral vaccines in patients with DiGeorge syndrome. Clinical Immunology, 113(1), 3–1. http://doi.org/10.1016/j.clim.2004.04.004
� 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: 906–11.
� 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), 1293–1302. http://doi.org/10.1016/j.jaci.2015.01.011