Immunologic Features 22q11 · DiGeorge Syndrome Cardiac anomalies Immunodeficiency Hypocalcemia from parathyroid gland hypoplasia Nomenclature The term 22q11.2 deletion syndrome is

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