Abstract
Purpose
We aimed to present the fetal ultrasound, cytogenetic/molecular testing and postmortem or postnatal clinical findings of cases with 22q11.2DS diagnosed prenatally.
Materials and methods
A retrospective medical record review of 48 prenatal cases diagnosed with 22q11.2DS were evaluated in our institution. Detailed ultrasound examination was performed on all fetuses. Postmortem and postnatal examinations were evaluated. The microdeletions were detected by karyotyping or microarray, then confirmed by FISH. Descriptive statistical analysis was performed.
Results
Demographic data of 48 prenatal cases including 46 singletons and 1 dichorionic diamniotic twin pregnancy were evaluated. The most common extracardiac anomaly was skeletal system anomalies (25%), in which PEV was the most frequent one (20.8%). Polyhydramnios rate was detected as 31%, in 6.6% as an isolated finding. Microdeletion has been detected by karyotyping in 13 cases (13/47, 27.7%) (including 2 unbalanced translocations), by FISH in 28 cases (28/48, 58.3%), by microarray/a-CGH testing in 7 cases. Microarray analysis showed that in one case with unbalanced translocation had two consecutive deletions; one was proximal and other one distal to critical region and not encompassing TBX1 gene but CRKL and LZTR1 genes.
Conclusion
The current study demonstrates the whole spectrum of atypical phenotypic and genotypic variations of 22q11.2DS in the largest prenatal case series reported to date. Therefore, differential diagnosis should be considered not solely in CHD, but also in the presence of isolated clubfeet and polyhydramnios. Establishing the diagnosis in the prenatal period may allow a postnatal multidisciplinary approach, as well as affect the actual prevalence of the disease.
Similar content being viewed by others
Availability of data and material
Data will be made available by the authors upon request.
References
Grati FR, Molina Gomes D, Ferreira JC et al (2015) Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies. Prenat Diagn 35(8):801–809. https://doi.org/10.1002/pd.4613
McDonald-McGinn DM, Sullivan KE (2011) Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore) 90(1):1–18. https://doi.org/10.1097/MD.0b013e3182060469
Maisenbacher MK, Merrion K, Pettersen B et al (2017) Incidence of the 22q11.2 deletion in a large cohort of miscarriage samples. Mol Cytogenet 10:6. https://doi.org/10.1186/s13039-017-0308-6
Botto LD, May K, Fernhoff PM et al (2003) A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112:101–107. https://doi.org/10.1542/peds.112.1.101
Gothelf D, Frisch A, Michaelovsky E, Weizman A, Shprintzen RJ (2009) Velo-cardio-facial syndrome. J Ment Health Res Intellect Disabil 2(2):149–167. https://doi.org/10.1080/19315860902756136
Edelmann L, Pandita RK, Morrow BE et al (1999) Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am J Hum Genet 64(4):1076–1086. https://doi.org/10.1086/302343
Shaikh TH, Kurahashi H, Saitta SC et al (2000) Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 9(4):489–501. https://doi.org/10.1093/hmg/9.4.489
Saitta SC, Harris SE, McDonald-McGinn DM et al (2004) Independent de novo 22q11.2 deletions in first cousins with DiGeorge/velocardiofacial syndrome. Am J Med Genet A 124A(3):313–317. https://doi.org/10.1002/ajmg.a.20421
Rauch A, Zink S, Zweier C et al (2005) Systematic assessment of atypical deletions reveals genotype–phenotype correlation in 22q11.2. Med Genet 42:871–876. https://doi.org/10.1136/jmg.2004.030619
Beaujard MP, Chantot S, Dubois M et al (2009) Atypical deletion of 22q11.2: detection using the FISH TBX1 probe and molecular characterization with high-density SNP arrays. Eur J Med Genet 52(5):321–327. https://doi.org/10.1016/j.ejmg.2009.05.010
Verhagen JM, Diderich KE, Oudesluijs G et al (2012) Phenotypic variability of atypical 22q11.2 deletions not including TBX1. Am J Med Genet A 158A(10):2412–2420. https://doi.org/10.1002/ajmg.a.35517
Rump P, de Leeuw N, van Essen AJ et al (2014) Central 22q11.2 deletions. Am J Med Genet A 164A(11):2707–2723. https://doi.org/10.1002/ajmg.a.36711
Bengoa-Alonso A, Artigas-Lopez M, Moreno-Igoa M et al (2016) Delineation of a recognizable phenotype for the recurrent LCR22-C to D/E atypical 22q11.2 deletion. Am J Med Genet Part A 170A:1485–1494. https://doi.org/10.1002/ajmg.a.37614
Zhang Z, Huynh T, Baldini A (2006) Mesodermal expression of Tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development. Development 133:3587–3595. https://doi.org/10.1242/dev.02539
Yagi H, Furutani Y, Hamada H et al (2003) Role of TBX1 in human del22q11.2 syndrome. Lancet 362:1366–1373. https://doi.org/10.1016/s0140-6736(03)14632-6
Gong W, Gottlieb S, Collins J et al (2001) Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects. J Med Genet 38(12):E45. https://doi.org/10.1136/jmg.38.12.e45
Zweier C, Sticht H, Aydin-Yaylagul I, Campbell CE, Rauch A (2007) Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. Am J Hum Genet 80:510. https://doi.org/10.1086/511993
Stalmans I, Lambrechts D, De Smet F et al (2003) VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nat Med 9:173–182
Besseau-Ayasse J, Violle-Poirsier C, Bazin A et al (2014) A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes. Prenat Diagn 34(5):424–430. https://doi.org/10.1002/pd.4321
Schindewolf E, Khalek N, Johnson MP et al (2018) Expanding the fetal phenotype: prenatal sonographic findings and perinatal outcomes in a cohort of patients with a confirmed 22q11.2 deletion syndrome. Am J Med Genet A 176(8):1735–1741. https://doi.org/10.1002/ajmg.a.38665
Noël AC, Pelluard F, Delezoide AL et al (2014) Fetal phenotype associated with the 22q11 deletion. Am J Med Genet A 164A(11):2724–2731. https://doi.org/10.1002/ajmg.a.36720
Bretelle F, Beyer L, Pellissier MCM et al (2010) Prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. Eur J Med Genet 53(6):367–370. https://doi.org/10.1016/j.ejmg.2010.07.008
Piliero LM, Sanford AN, McDonald-McGinn DM, Zackai EH, Sullivan KE (2004) T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome. Blood 103(3):1020–1025. https://doi.org/10.1182/blood-2003-08-2824
Bassett AS, McDonald-McGinn DM, Devriendt K et al (2011) International 22q11.2 Deletion Syndrome Consortium. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr 159(2):332.e1-339.e1. https://doi.org/10.1016/j.jpeds.2011.02.039
Chaoui R, Kalache KD, Heling KS, Tennstedt C, Bommer C, Körner H (2002) Absent or hypoplastic thymus on ultrasound: a marker for deletion 22q11.2 in fetal cardiac defects. Ultrasound Obstet Gynecol 20(6):546–552. https://doi.org/10.1046/j.1469-0705.2002.00864.x
Paladini D (2011) How to identify the thymus in the fetus: the thy-box. Ultrasound Obstet Gynecol 37(4):488–492. https://doi.org/10.1002/uog.8854
Chaoui R, Heling KS, Lopez AS, Thiel G, Karl K (2011) The thymic-thoracic ratio in fetal heart defects: a simple way to identify fetuses at high risk for microdeletion 22q11. Ultrasound Obstet Gynecol 37(4):397–403. https://doi.org/10.1002/uog.8952
Boudjemline Y, Fermont L, Le Bidois J, Lyonnet S, Sidi D, Bonnet D (2001) Prevalence of 22q11 deletion in fetuses with conotruncal cardiac defects: a 6-year prospective study. J Pediatr 138(4):520–524. https://doi.org/10.1067/mpd.2001.112174
Lamouroux A, Mousty E, Prodhomme O et al (2016) Absent or hypoplastic thymus: a marker for 22q11.2 microdeletion syndrome in case of polyhydramnios. J Gynecol Obstet Biol Reprod 45(4):388–396. https://doi.org/10.1016/j.jgyn.2015.04.015
McDonald-McGinn DM, Sullivan KE, Marino B et al (2015) 22q11.2 deletion syndrome. Nat Rev Dis Primers 1:15071. https://doi.org/10.1038/nrdp.2015.71
Sacca R, Zur KB, Crowley TB et al (2017) Association of airway abnormalities with 22q11.2 deletion syndrome. Int J Pediatr Otorhinolaryngol 96:11–14. https://doi.org/10.1016/j.ijporl.2017.02.012
Dashe JS, Pressman EK, Hibbard JU (2018) Society for Maternal-Fetal Medicine (SMFM) Consult Series #46: evaluation and management of polyhydramnios. Am J Obstet Gynecol 219(4):B2–B8. https://doi.org/10.1016/j.ajog.2018.07.016
Hillman SC, Pretlove S, Coomarasamy A et al (2011) Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 37(1):6–14. https://doi.org/10.1002/uog.7754
(2016) Practice Bulletin No. 162: Prenatal diagnostic testing for genetic disorders. Obstet Gynecol 127(5):e108–e122. https://doi.org/10.1097/AOG.0000000000001405
Homans JF, Tromp IN, Dino C et al (2018) Orthopedic manifestations within the 22q11.2 deletion syndrome: a systematic review. Am J Med Genet 176A:2104–2120. https://doi.org/10.1002/ajmg.a.38545
Digilio MC, Angioni A, De Santis M et al (2003) Spectrum of clinical variability in familial deletion 22q11.2: from full manifestation to extremely mild clinical anomalies. Clin Genet 63:308–313. https://doi.org/10.1034/j.1399-0004.2003.00049.x
Homans JF, Crowley TB, Chen E et al (2018) Clubfoot in association with the 22q11.2 deletion syndrome: an observational study. Am J Med Genet 176A:2135–2139. https://doi.org/10.1002/ajmg.a.40649
Society for Maternal-Fetal Medicine, McKinney J, Rac MWF, Gandhi M (2019) Congenital talipes equinovarus (clubfoot). Am J Obstet Gynecol 221(6):B10–B12. https://doi.org/10.1016/j.ajog.2019.09.022
Lindsay EA, Vitelli F, Su H et al (2001) Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410(6824):97–101. https://doi.org/10.1038/35065105
Momma K (2010) Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome. Am J Cardiol 105(11):1617–1624. https://doi.org/10.1016/j.amjcard.2010.01.333
Umeki I, Niihori T, Abe T et al (2019) Delineation of LZTR1 mutation positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. Hum Genet 138(1):21–35. https://doi.org/10.1007/s00439-018-1951-7
Steklov M, Pandolfi S, Baietti MF et al (2018) Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. Science 362:1177–1182. https://doi.org/10.1126/science.aap7607
Guris DL, Duester G, Papaioannou VE, Imamoto A (2006) Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Dev Cell 10(1):81–92. https://doi.org/10.1016/j.devcel.2005.12.002
Taddei I, Morishima M, Huynh T, Lindsay EA (2001) Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q11 syndromes. Proc Natl Acad Sci USA 98(20):11428–11431. https://doi.org/10.1073/pnas.201127298
Voss AK, Vanyai HK, Collin C et al (2012) MOZ regulates the Tbx1 locus, and Moz mutation partially phenocopies DiGeorge syndrome. Dev Cell 23(3):652–663. https://doi.org/10.1016/j.devcel.2012.07.010
Goodship J, Cross I, Scambler P, Burn J (1995) Monozygotic twins with chromosome 22q11.2 deletion and discordant phenotype. J Med Genet 32:746–748. https://doi.org/10.1136/jmg.32.9.746
Fryer A (1996) Monozygotic twins with 22q11 deletion and discordant phenotypes. J Med Genet 33(2):173. https://doi.org/10.1136/jmg.33.2.173
Rauch A, Hofbeck M, Bahring S et al (1998) Monozygotic twins concordant for Cayler syndrome. Am J Med Genet 75:113–117 (PMID: 9450869)
Hillebrand G, Siebert R, Simeoni E, Santer R (2000) DiGeorge syndrome with discordant phenotype in monozygotic twins. J Med Genet 37(9):E23. https://doi.org/10.1136/jmg.37.9.e23
Singh SM, Murphy B, O’Reilly R (2002) Monozygotic twins with chromosome 22q11 deletion and discordant phenotypes: updates with an epigenetic hypothesis. J Med Genet 39(11):e71. https://doi.org/10.1136/jmg.39.11.e71
Gul A, Gungorduk K, Turan I, Yildirim G, Gedikbasi A, Ozdemir A (2013) Prenatal diagnosis of 22q11.2 deletion syndrome in twin pregnancy: a case report. J Clin Ultrasound 41:6–9. https://doi.org/10.1002/jcu.21992
Halder A, Jain M, Chaudhary I, Varma B (2012) Chromosome 22q11.2 microdeletion in monozygotic twins with discordant phenotype and deletion size. Mol Cytogenet 5:13. https://doi.org/10.1186/1755-8166-5-13
IPDTOC Working Group (2011) Prevalence at birth of cleft lip with or without cleft palate: data from the International Perinatal Database of Typical Oral Clefts (IPDTOC). Cleft Palate Craniofac J 48(1):66–81. https://doi.org/10.1597/09-217
Faure JM, Mousty E, Bigorre M et al (2020) Prenatal ultrasound diagnosis of cleft palate without cleft lip, the new ultrasound semiology. Prenat Diagn 40(11):1447–1458. https://doi.org/10.1002/pd.5794
Funding
None.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by TSS, UA, MK and BK. The manuscript was written by TSS, AY, RH and SB. TSS, IHK and RH analyzed and interpreted of the data.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
The study protocol was approved by our institutional review board.
Consent to participate
All subjects provided written informed consent.
Consent for publication
All authors agree on the final manuscript and the order of authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Sarac Sivrikoz, T., Basaran, S., Has, R. et al. Prenatal sonographic and cytogenetic/molecular findings of 22q11.2 microdeletion syndrome in 48 confirmed cases in a single tertiary center. Arch Gynecol Obstet 305, 323–342 (2022). https://doi.org/10.1007/s00404-021-06125-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00404-021-06125-4