DiGeorge syndrome (Chromosome 22q11.2 deletion syndrome): A historical perspective with review of 66 patients

Abstract

Aim: Congenital heart defects (CHD) are the most common major birth defects in humans. Conotruncal cardiac defects (CCD) and aortic arch anomalies, the outflow tract anomalies of the heart, usually accompany dysmorphic syndromes. Di George Syndrome, deletion of 22q11.2, is one of the typical examples for this entity. Our study was designed to determine the frequency of 22q11.2 deletion in a retrospectively ascertained sample of patients with conotruncal cardiac defects and structural cardiac defects accompanying other clinical findings of 22q11.2 deletion syndrome.

Methods: A total of 66 patients (4 days-16.6 years; mean 38 months), 56 followed with the diagnosis of conotruncal cardiac defects and 10 having congenital cardiac defects other than conotruncal abnormalities participated to our study . All patients underwent karyotype and Fluorescence in Situ Hybridization (FISH) analysis for 22q11.2 deletion. After the detection of the deletion a follow up protocol was formed for the patients

Results: Five of all patients were found to have the deletion positive (7.6%). Four of them had conotruncal cardiac defects. All patients having 22q11.2 deletion had at least one abnormality of the syndrome other than cardiac problems. Facial dysmorphism and growth retardation were the most common features .Cognitive disability, feeding problems, hypocalcemia, psychiatric problems, immunity differences were the other associated problems. Parental evaluation yielded one mother to be a deletion carrier.

Conclusion: We suggest that 22q11.2 deletion must be explored in all newborns with selective conotruncal cardiac defects and with non- conotruncal cardiac defects accompanying the other anomalies of the syndrome. All deletion positive patients must be evaluated for the accompanying features of the syndrome with genetic counselling.

Keywords

• 22q11.2 deletion,Conotruncal anomalies,Fluorescence in Situ Hybridization

DiGeorge Sendromu (Kromozom 22q11.2 delesyon sendromu): Altmış altı hastanın incelendiği tarihsel perspektif

Abstract

Amaç: Doğumsal kalp hastalıkları insanlarda en sık görülen konjenital anomalilerdir. Kalbin çıkış yolu anomalileri olan konotrunkal kalp hastalıkları ve aort arkı anomalileri genellikle dismorfik sendromlara eşlik eder. 22q11.2 delesyon sendromu bu klinik durumun tipik örneklerindendir. Bu çalışma konotrunkal kalp anomalileri ve 22q11. 2 delesyon sendromunun diğer klinik bulgularının eşlik ettiği doğumsal kalp hastalıklarında 22q11.2 delesyon sıklığını araştırmak amacıyla planlanmıştır.

Yöntem: Yaşları 4 gün ile 16.6 yaş arasında değişen 56 konotrunkal kalp anomalili, 10 yapısal kalp anomalisi ile sendromun diğer klinik bulgularının eşlik ettiği 66 hasta çalışmaya katıldı. Tüm hastalara karyotip analizi uygulandı, Floresan in situ hibridizasyon yöntemiyle delesyon tarandı. Pozitif saptanan hastalar için klinik izlem protokolü oluşturuldu.

Bulgular: Hastaların %7.6 (n=5) delesyon saptandı. Dördü konotrunkal kalp anomalileri grubundandı. Tüm hastalarda kalp anomalisine ek olarak sendromun diğer klinik bulgularından en az biri mevcuttu. Fasiyal dismorfizm ve gelişme geriliği en sık saptanan klinik sorunlardı. Kognitif yetersizlik, beslenme sorunları, hipokalsemi, psikiyatrik sorunlar, bağışıklık sisteminde değişiklikler saptanan diğer klinik bulgulardı. Ebeveyn değerlendirmesi sonucunda bir annede de delesyon pozitifliği saptandı.

Sonuç: Tüm seçilmiş konotrunkal kalp anomalisi olan olgularda ve sendromun diğer anomalilerinin saptandığı kalp anomalili olgularda 22q11.2 delesyonun taranması gerektiği düşünülmektedir. Delesyon pozitifliği bulunan tüm olgular diğer anomaliler açısından da değerlendirlmeli ve genetik danışma sağlanmalıdır.

Keywords

• 22q11.2 delesyonu,konotrunkal anomaliler,Floresan in situ hibridizasyon

References

1. 1. Fahed AC, Gelb BD, Seidman JG, Seidman CE.. Genetics of congenital heart disease: the glass half empty. Circ Res. 2013;112:707–20.
2. 2. Azamian M, Lalani SR. Cytogenomic Aberrations in congenital cardiovascular malformations. Mol Syndromol. 2016;7:51–61.
3. 3. Grati FR, Molina Gomes D, Ferreira JC, Dupont C, Alesi V, Gouas L, et al. Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies. Prenat Diagn. 2015;35:801–9.
4. 4. Thomas J. A, Graham J.M Jr. Chromosome 22q11 deletion syndrome: An update and review for the primary pediatrician. ClinPediatr (Phila). 1997;36:253- 66.
5. 5. Goldmuntz E. Di George Syndrome: new insights. Clin Perinatol. 2005;32:963-78.
6. 6. Henderson LB, Applegate CD, Wohler E, Sheridan MB, Hoover-Fong J, Batista DA. The impact of chromosomal microarray on clinical management: a retrospective analysis. Genet Med. 2014;16:657–64.
7. 7. Wonkam A, Tokoy R, Cheloy D, Tekendo-Ngongang C, Kingue S, Dahoun S. The 22q11.2 Deletion Syndrome in Congenital Heart Defects: Prevalence of Microdeletion Syndrome in Cameroon. Glob Heart. 2017;12:115-20.
8. 8. Goldmuntz E. The epidemiology and genetics of congenital heart disease. Clin Perinatol. 2001;28:1–11.

9. 9. Giray O, Ulgenalp U, Bora E, Sagın Saylam G, Unal N, Meşe T, et al. Congenital cardiac defects with 22q11 deletion. Turk J Pediatr. 2003;4:217–20.
10. 10. Clark EB. Mechanism in the pathogenesis of congenital heart defects. In: Pierpont ME, Moller J, eds. The Genetics of Cardiovascular Disease. Boston: Martinus- Niijoff Co, 1986. pp. 3–11.
11. 11. Layela A, Delneste D, Pradier O, Hans C, Darboux R, Ogur G. Giant platelets in a case of deletion 11q24-qter confirmed by Fluorescence In Situ Hybridization. Am J Med Genet. 2002;110:170–5.
12. 12. Ogur G, Van Assche E, Vegetti W, Verheyen G, Tournaye H, Bonduelle M, et al. Chromosomal segregation in spermatozoa of 14 Robertsonian translocation carriers. Mol Hum Reprod. 2006;12:209–15.
13. 13. Tobias ES, Morrison N, Whiteford ML,Tolmie JL. Towards earlier diagnosis of 22q11 deletions. Arch Dis Child. 1999;81:513-4.
14. 14. Lanzkowsky P. Manual of Pediatric Hematology and Oncology. 1st ed. California: Academic Press; 2000.
15. 15. Nicholson JF, Pesce MA. Reference Ranges For Laboratory Tests and Procedures. In:Behrman R, Kliegman R, Jenson H, eds. Nelson Textbook of Pediatrics (17th ed) Philadelphia: WB Saunders Co; 2004. pp. 2393–427.
16. 16. Glover TW. CATCHing a break on 22. Nat Genet. 1995;10:257- 8.
17. 17. Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, et al. A population-based study of the 22q11.2 deletion: Phenotype, incidence, and contribution to major birth defects in the population. Pediatrics. 2003;112:101–7.
18. 18. Digilio MC, Angioni A, De Santis M, Lombardo A, Giannotti A, Dallapiccola B, et al. Spectrum of clinical variability in familial deletion 22q 11. 2: from full manifestation to extremely mild clinical anomalies. Clin Genet. 2003;63:308-13.
19. 19. Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, et al. Spectrum of clinical features associated with inter¬stitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997;34:798-804.
20. 20. Park I, Ko JK, Kim YH, Yoo HW, Seo EJ, Choi JY, et al. Cardiovascular anomalies in patients with chromosome 22q11.2 deletion: a Korean multicenter study. Int J Cardiol. 2006;114:230–5.
21. 21. Goldmuntz E, Clark BJ, Mitchell LE, Jawad AF, Cuneo BF, Reed L, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol. 1998;32:492–8.
22. 22. Hashish MM, El-Belbesy MF, Abdalla E, Abdel- Mohsen. Detection of Chromosome 22q11 Microdeletions Among Children With Isolated Congenital Heart Disease using PCR. Alex J Pediatr. 2005;19:403-9.
23. 23. Shen L, Xu YJ, Zhao PJ, Sun K. Chinese Journal of Contemporary Pediatrics. 2009;11:25-8.
24. 24. Khositseth A, Tocharoentanaphol C, Khowsathit P, Ruangdaraganon N. Chromosome 22q11 deletions in patients with conotruncal heart defects. Pediatr Cardiol. 2005;26:570-3.
25. 25. Derbent M, Yilmaz Z, Baltaci V, Saygılı A, Varan B, Tokel K. Chromosome 22q11.2 deletion and phenotypic features in 30 patients with conotruncal heart defects. Am J Med Genet A. 2003;116A:129-35.
26. 26. Kinouchi A, Mori K, Ando M, Takao A. Facial appearance of patients with conotruncal abnor¬malities. Pediatr Jpn. 1976;17:84.
27. 27. Brauner R, Le Harivel de Gonneville A, Kindermans C, Le Bidois J, Prieur M, Lyonnet S, et al. Parathyroid function and growth in 22q11.2 deletion syndrome. J Pediatr. 2003;142:504-8.
28. 28. Müftüoğlu E. İmmünoloji, Immunology .1st ed. İzmir: Saray Kitabevi, 1993; 15- 44. Turkish.
29. 29. Seçmeer G. İmmün yetmezliği olan çocukların aşılanması Immunization of immunsupressed children. Katkı Pediatri Dergisi 2006;28:800–10.
30. 30. Sullivan KE, Burrows E, McDonald McGinn DM. Healthcare utilization in chromosome 22q11.2 deletion patients with cardiac disease and low Tcell counts. Am J Med Genet A. 2016;170:1630-4 .
31. 31. Dyce O, McDonald-McGinn D, Kirschner RE, Zackai E, Young K, Jacobs IN. Otolaryngologic manifestations of the 22q11.2 deletion syndrome. Arch Otolaryngol Head Neck Surg. 2002;128(12):1408-12.
32. 32. Nouri N, Memarzadeh M, Salehi M, Nouri N, Meamar R, Behnam M et al. Prevalance of 22q11.2 microdeletion syndrome in Iranian patients with cleft palate. Adv Biomed Res. 2016;5:201.
33. 33. Latger-Cannard V, Bensoussan D, Grégoire MJ, Marcon F, Cloez JL, Leheup B, et al. Frequency of trombocytopenia and large platelets correlates neither with conotruncal cardiac anomalies nor immunological features in chromosome 22q11.2 deletion syndrome. Eur J Pediatr. 2004;163:327–8.
34. 34. Naqvi N, Davidson SJ, Wong D, Cullinan P, Roughton M, Doughty VL, et al. Predicting 22q11.2 deletion syndrome: a novel method using the routine full blood count. Int J Cardiol. 2011;150:50-3.
35. 35. Murphy KC. Annotation: Velo-cardiofacial syndrome. J Child Psychol Psychiatry. 2003;46: 563–71.
36. 36. Murphy KC, Jones, LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999;56:940–5.
37. 37. Weisman O, Guri Y, Gur RE, McDonald-McGinn DM, Calkins ME, Tang SX et al. Subthreshold psychosis in 22q11.2 deletion syndrome: Multisite naturalistic study. Schizophr Bull. 2017;43:1079-89.
38. 38. Rauch A, Zink S, Zweier C, Thiel C, Koch A, Rauch R, et al. Systemic assessment of atypical deletions reveals genotype- phenotype correlation in 22q11.2 J Med Genet. 2005;42:871-6.
39. 39. Greenhalgh KL, Aligianis IA, Bromilow G, Cox H, Hill C, Stait, et al. 22q11 deletion: a multisystem disorder requiring multidisciplinary input. Arch Dis Child. 2003;88:523–4.
40. 40. Cuneo BF. 22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes. Curr Opinion Pediatr. 2001;13: 465-72.