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Rare case of patient with DiGeorge syndrome and limbs anomalies: the benefit of SNP microarray analysis?


Authors: A. Hladíková 1;  P. Plevová 1;  A. Balcar 1;  D. Černá 1;  P. Tvrdá 1;  E. Šilhánová 1;  D. Grečmalová 1;  A. Křepelová 2
Authors‘ workplace: Oddělení lékařské genetiky FN, Ostrava primářka MUDr. E. Šilhánová 1;  Ústav biologie a lékařské genetiky 2. LF UK a FN Motol, Praha přednosta prof. MUDr. M. Macek Jr., DrSc. 2
Published in: Čes-slov Pediat 2015; 70 (5): 293-301.
Category: Case Report

Overview

DiGeorge syndrome (velocardiofacial syndrome, VCFS, 22q11DS) is caused by a microdeletion of approximately 40 genes from one copy of chromosome 22. Expression of the syndrome is a variable combination of more than 190 phenotypic characteristics, the most common are congenital heart disease, cleft palate and velopharyngeal insufficiency. Limb anomalies of hands and feets are not a typical clinical symptoms of DiGeorge syndrome.

The aim of the study was to evaluate the extent of genomic changes in a 4.5 years old child with classical phenotypic features of 22q11DS in combination with severe ectrodactyly of all four limbs in addition; using microarray based single nucleotide polymorphism techniques in order to explain the origin of limb anomaly defects. FISH analysis, TP63 gene sequencing and whole genome SNP array analysis using HumanCytoSNP-12 DNA Analysis Beadchip (Illumina Inc.) were performed. FISH method revealed DiGeorge syndrome, TP63 gene sequencing did not detect any deleterious mutation, microarray SNP analysis established microdeletion of 22q11.2 region in standard defined range of 2,9 Mb. The original possible hypothesis, that in a patient it could exist a much more genomic changes than only these related to 22q11.2 region, involving genes associated with limb development and formation and thus explaining devastating limbs damage in patient, unfortunately was not confirmed. Although limb defects do not belong to the typical pathogenic signs of DiGeorge syndrome, this diagnosis should be considered in all neonate with congenital heart defect, cleft palate and limb anomalies. Even though variable phenotypical expressivity in DiGeorge syndrome is frequent, we can not exclude the possibility of coincidence of two independent genetic defects in our patient; DiGeorge syndrome due to 22q11.2 microdeletion and ectrodactyly which results of another gene/s mutation.

Key words:
DiGeorge syndrome, 22q11.2 deletion syndrome, VCFS, SNP microarray, ectrodactyly, syndactyly


Sources

1. Shprintzen RJ, Higgins AM, Antshel K, et al. Velo-cardio-facial syndrome. Curr Opin Pediatr 2005; 17 (6): 725–730.

2. Robin NH, Shprintzen RJ. Defining the clinical spectrum of deletion 22q11.2. J Pediatr 2005; 147 (1): 90–96.

3. Schinke M, Izumo S. Deconstructing DiGeorge syndrome. Nat Genet 2001; 7 (3): 238–240.

4. Óskarsdóttir 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: 148–151.

5. Morrow B, Goldberg R, Carlson C, et al. Molecular definition of the 22q11 deletions in velo-cardiofacial syndrome. Am J Hum Genet 1995; 56 (6): 1391–1403.

6. Carlson C, Sirotkin H, Pandita R, et al. Molecular definition of 22q11 deletions in 151 velo-cardiofacial syndrome patients. Am J Hum Genet 1997; 61 (3): 620–629.

7. Friedman MA, Miletta N, Roe CH, et al. Cleft palate, retrognathia and congenital heart disease in velo-cardio-facial syndrome: a phenotype correlation study. Int J Pediatr Otorhinolaryngol 2011; 75 (9): 1167–1172.

8. Edelmann L, Pandita RK, Morrow BE. Low-copy repeats mediate the common 3-mb deletion in patients with velo-cardio-facial syndrome. Am J Hum Genet 1999; 64 (4): 1076–1086.

9. Shaikh TH, Kurahashi H, Saitta SC, et al. Chromosome 22 – specific low copy repeats and the 22q11.2 deletion syndrome: Genomic organization and deletion endpoint analysis. Hum Mol Genet 2000; 9 (4): 489–501.

10. Maynard TM, Haskell GT, Lieberman JA, et al. 22q11 DS: genomic mechanisms and gene function in DiGeorge/velocardiofacial syndrome. Int J Dev Neurosci 2002; 20: 407–419.

11. Firth HV, Hurst JA, Hall JG, et al. Velocardiofacial syndrome 22q11del syndrome. Oxford desk Reference: Clinical Genetics. Oxford, UK: Oxford University Press, 2009: 490–492.

12. Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 1998; 32 (2): 492–498.

13. Marino B, Digilio MC, Toscano A, et al. Anatomic patterns of conotruncal defects associated with deletion 22q11. Genet Med 2001; 3 (1): 45–48.

14. Momma K. Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome. Am J Cardiol 2010; 105 (11): 1617–1624.

15. Khositseth A, Tocharoentanaphol C, Khowsathit P, et al. Chromosome 22q11 deletions in patients with conotruncal heart defects. Pediatr Cardiol 2005; 26 (5): 570–573.

16. Varga I, Plank L, Mešťanová V, et al. Prehľad a návrh klasifikácie vrodených anomálií týmusu u detí. Čes-slov Pediat 2014; 69 (3): 178–190.

17. Emanuel BS, McDonald-McGinn D, Saitta SC, et al. The 22q11.2 deletion syndrome. Adv Pediatr 2001; 48: 39–73.

18. Antshel KM, Kates WR, Roizen N, et al. 22q11.2 deletion syndrome: genetics, neuroanatomy and cognitive/behavioral features keywords. Child Neuropsychol 2005; 11 (1): 5–19.

19. Bassett AS, Marshall CR, Lionel AC, et al. Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome. Hum Mol Genet 2008; 24 (17): 4045–4053.

20. Yang Ch, Huang CHH, Cheon ML, et al. Unambiguous molecular detections with multiple genetic approach for the complicated chromosome 22q11 deletion syndrome. BMC Medical Genetics 2009; 10: 16.

21. Vokurková J, Elstnerová L, Lukášová O, et al. Vývoj neonatální péče a zhodnocení zkušeností prvních pěti let operací rozštěpu rtu v neonatálním období. Čes-slov Pediat 2011; 66 (6): 356–362.

22. Wilson DI, Burn J, Goodship J. DiGeorge syndrome: part of CATCH 22. J Med Genet 1993; 30: 852–856.

23. Cormier-Daire V, Iserin L, Theophile D, et al. Upper limb malformations in DiGeorge syndrome. Am J Med Genet 1995; 56: 39–41.

24. Prasad C, Quackenbush EJ, Whiteman D, et al. Limb anomalies in DiGeorge and CHARGE syndromes. Am J Med Genet 1997; 68: 179–181.

25. Kokitsu-Nakata NM, Guion-Almeida ML, Richieri-Costa A. 22q11 deletion syndrome and limb anomalies: report on two brazilian patients. Cleft Palate Craniofac J 2008; 45 (5): 561–566.

26. Al-Hertani W, Hastings VA, McGowan-Jordan J, et al. Severe craniosynostosis in an infant with deletion 22q11.2 syndrome. Am J Med Genet 2012; 161A: 153–157.

27. Ming JE, McDonald-McGinn DM, Megerian TE, et al. Skeletal anomalies and deformities in patients with deletions of 22q11. Am J Med Genet 1997; 72: 210–215.

28. O´Driscoll MC, Clayton-Smith J. Bilateral camptodactyly and recurrent patellar dislocation: a new sign of 22q11 deletions or an independent dominant disorder? Clin Dysmorphol 2008; 17: 157–159.

29. Brites MM. Familial camptodactyly. Eur J Dermatol 1998; 8: 355–356.

30. Lammer EJ, Opitz JM. The DiGeorge anomaly as a developmental field defect. Am J Med Genet 1986; 2: 113–127.

31. Le Douarin N. Migration and differentiation of neural crest cells. Curr Top Dev Biol 1980; 16: 31–85.

32. Zheng D, Zhang Z, Harrison PM, et al. Integrated pseudogene annotation for human chromosome 22: evidence for transcription. J Mol Biol 2005; 349: 27–45.

33. Thuresson AC, Bondeson ML, Edeby C, et al. Whole-genome array-CGH for detection of submicroscopic chromosomal imbalances in children with mental retardation. Cytogenet Genome Res 2007; 118 (1): 1– 7.

34. Erickson RP, de Ståhl T, Bruder CE, et al. A patient with 22q11.2 deletion and Opitz syndrome-like phenotype has the same deletion as velocardiofacial patients. Am J Med Genet A 2007; 143A (24): 3302–3308.

35. Ben-Shachar S, Ou Z, Shaw CA, et al. 22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome. Am J Hum Genet 2008; 82 (1): 214–221.

36. Giele H, Cassell O. Plastic and Reconstructive Surgery. Oxford: Oxford University Press, 2008: 1–197.

37. Moerman P, Fryns JP. Ectodermal dysplasia, Rapp-Hodgkin type in a mother and severe ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC) in her child. Am J Med Genet 1998; 63 (3): 479–481.

38. Duijf PHG, van Bokhoven H, Brunner H. Pathogenesis of split-hand//split-foot malformation. Hum Mol Genet 2003;12 (1): 51–60.

39. Winter RM, Baraitser M. The London dysmorphology database. J Med Genet 1987; 24 (8): 509–510.

40. Weksberg R, Hughes S, Moldovan L, et al. A method for accurate detection of genomic microdeletions using real-time quantitative PCR. BMC Genomics 2005; 6: 180.

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