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
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—
—
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Juvenile rheumatoid arthritis
Immune thrombocytopenia
Autoimmune hemolytic anemia
Inflammatory Bowel Disease (e.g. Celiac disease)
—  Adults
—
—
—
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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
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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.
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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.
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DiGeorge AM. Discussions on a new concept of the cellular basis of immunology. J Pediatr 1965; 67: 907.
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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.
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Hacıhamdioğlu, B., Hacıhamdioğlu, D., & Delil, K. (2015). 22q11 deletion syndrome: current perspective. The Application of
Clinical Genetics, 8, 123–132.
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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.
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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.
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Kobrynski, L. J., & Sullivan, K. E. (2007). Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion
syndromes. The Lancet, 370(9596), 1443–1452.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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