22q11.2 deletion syndrome: 20 years of experience from two pediatric immunology units and review of clues for diagnosis and disease management

Main Article Content

Selime Ozen
Omer Akcal
Ilke Taskirdi
Idil Akay Haci
Neslihan Edeer Karaca
Nesrin Gulez
Guzide Aksu
Ferah Genel
Necil Kutukculer

Keywords

infections, immunodeficiency, thymus., pediatric, 22q11.2 deletion syndrome

Abstract

Introduction and objectives: The purpose of this study was to evaluate patients diagnosed with 22q11.2 deletion syndrome and determine the clues directing to diagnosis and evaluation of immunological findings for excellent management of the disease.


Material and methods: Thirty-three pediatric patients with 22q11.2 deletion syndrome diag-nosed between 1998 and 2019 at Pediatric Immunology Division of Ege University Faculty of Medicine and SBU Izmir Dr Behcet Uz Children’s Education and Research Hospital were evaluated.


Results: This study includes the largest case series reported from Turkey. Congenital car-diac anomalies were the most common pathology associated with the syndrome (90.9%). Hypocalcemic symptoms were observed in 13 patients (40%). Twenty-two of the 33 (66.6%) patients were diagnosed before two years of age. Autoimmune diseases, dysmorphic facial findings, recurrent infections, growth retardation, and speech impairment were other clues for diagnosis in older patients. Clinical spectrum and immunological abnormalities of this syn-drome are quite variable. All T-cell subset counts were less than 5th percentile below median by age in one patient (3%) and 10 patients had normal all T-cell subset counts (30.3%). Overall, 69.6% of the patients had normal IgG, IgA, and IgM levels and two patients had panhypogam-maglobulinemia. Recurrent infections were revealed in 75.7% of the patients during follow-up.


Conclusions: Presence of cardiac anomaly is more helpful in the diagnosis, especially under two years of age. Patients with immunologically high or standard risk did not show any differ-ence in terms of numbers and severity of infections and autoimmunity.

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References

1. Oskarsdóttir S, Vujic M, Fasth A. Incidence and prevalence of the 22q11 deletion syndrome: A population-based study in western Sweden. Arch Dis Child. 2004;89(2):148–51. https:// doi.org/10.1136/adc.2003.026880

2. Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: Outcome of 44 consecutive transplants. Blood. 2007;109(10):4539–47. https://doi.org/10.1182/blood-2006-10-048652

3. Sullivan KE, Jawad AF, Randall P, Driscoll DA, Emanuel BS, McDonald-McGinn DM, et al. Lack of correlation between impaired T cell production, immunodeficiency and other phenotypic features in chromosome 22q11.2 deletion syndromes. Clin Immunol Immunopathol. 1998;86(2):141–6. https://doi. org/10.1006/clin.1997.4463

4. Rozas MF, Benavides F, Leon L, Repetto M. Association between phenotype and deletion size in 22q11.2 microdeletion syndrome: Systematic review and meta-analysis. Orphanet J Rare Dis. 2019;14:195–204. https://doi.org/10.1186/ s13023-019-1170-x

5. Aksu A, Genel F, Koturoglu G, Kurugol Z, Kutukculer N. Original serum immunoglobulin (IgG, IgM, IgA) and IgG subclass concentrations in healthy children: A study using nephelometric technique. Turkish J Pediatr. 2006;48(1):19–24. PMID: 16562781

6. Comans-Bitter WM, Groot R, Beemd R, Neijens HJ, Hop W CJ, Groeneveld K, et al. Immunophenotyping of blood lymphocytes in childhood reference values for lymphocyte subpopulations. J Pediatr. 1996;130(3):388–93. https://doi.org/10.1016/ S0022-3476(97)70200-2

7. Cancrini C, Puliafito P, Digilio MC, Soresina A, Martino S, Rondelli R, et al. Clinical features and follow-up in patients with 22q11.2 deletion syndrome. J Pediatr. 2014;164(6):1475– 80. https://doi.org/10.1016/j.jpeds.2014.01.056

8. McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JAS, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:1–19. https://doi.org/10.1038/nrdp.2015.71

9. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: The chromosome 22q11.2 deletion syndromes. Lancet. 2007;370:1443–52. https://doi.org/10.1016/ S0140-6736(07)61601-8

10. McDonald-McGinn DM, Tonnesen MK, Laufer-Cahana A, Finucane B, Driscoll DA, Emanuel BS, et al. Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: Cast a wide FISHing net! Genet Med. 2001;3(1):23–9. https://doi.org/10.1097/00125817-200101000-00006

11. Repetto GM, Guzmán ML, Delgado I, Loyola H, Palomares M, Lay-Son G, et al. Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: A retrospective cohort study. BMJ Open. 2014;4(11):e005041. https://doi. org/10.1136/bmjopen-2014-005041

12. McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore). 2011;90(1):1–18. https://doi. org/10.1097/MD.0b013e3182060469

13. Fung WLA, Butcher NJ, Costain G, Andrade DM, Boot E, Chow EWC, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. Genet Med. 2015;17:599–609. https://doi.org/10.1038/gim.2014.175

14. Haskologlu ZS, Ikinciogullari A. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Turk J Immunol. 2014;2:57–66. https://doi.org/10.5606/tji. 2014.320

15. Bohm LA, Zhou TC, Mingo TJ, Dugan SL, Patterson RJ, Sidman JD, et al. Neuroradiographic findings in 22q11.2 deletion syndrome. Am J Med Genet A. 2017;173:2158–65. https://doi. org/10.1002/ajmg.a.38304

16. Robin NH, Taylor CJ, McDonald-McGinn DM, Zachai EH, Bingham P, Collins KJ, et al. Polymicrogyria and deletion 22q11.2 syndrome: Window to the etiology of a common cortical malformation. Am J Med Genet A. 2006;140(22):2416–25. https://doi.org/10.1002/ajmg.a.31443

17. Schaer M, Glaser B, Cuadra MB, Debbane M, Thiran JP, Eliez S. Congenital heart disease affects local gyrification in 22q11.2 deletion syndrome. Dev Med Child Neurol. 2009;51(9):746–53. https://doi.org/10.1111/j.1469-8749.2009.03281.x

18. McLean-Tooke A, Barge D, Spickett GP, Gennery AR. Immunologic defects in 22q11.2 deletion syndrome. J Allergy Clin Immunol. 2008;122(2):362–7. https://doi.org/10.1016/j. jaci.2008.03.033

19. Nain E, Kiykim A, Ogulur I, Kasap N, Karakoc-Aydiner E, Ozen A, et al. Immune system defects in DiGeorge syndrome and association with clinical course. Scand J Immunol. 2019;90(5):e12809. https://doi.org/10.1111/sji.12809

20. Suksawat Y, Sathienkijkanchai A, Veskitkul J, Jirapongsananuruk O, Visitsunthorn N. Resolution of primary immune defect in 22q11.2 deletion syndrome. J Clin Immunol. 2017;37(2):375–82. https://doi.org/10.1007/s10875-017-0394-6

21. Giardino G, Radwan N, Koletsi P, Morrogh DM, Adams S, Ip W, et al. Clinical and immunological features in a cohort of patients with partial DiGeorge syndrome followed at a single center. Blood. 2019;133:2586–96. https://doi.org/10.1182/ blood.2018885244