Clinical and Experimental Pediatrics

대한소아청소년과학회 (The Korean Pediatric Society)
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The strong association of left-side heart anomalies with Kabuki syndrome

  • Yoon, Ja Kyoung (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Ahn, Kyung Jin (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Kwon, Bo Sang (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Kim, Gi Beom (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Bae, Eun Jung (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Noh, Chung Il (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Ko, Jung Min (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine)
  • 투고 : 2014.07.30
  • 심사 : 2014.09.26
  • 발행 : 2015.07.10
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초록

Purpose: Kabuki syndrome is a multiple congenital malformation syndrome, with characteristic facial features, mental retardation, and skeletal and congenital heart anomalies. However, the cardiac anomalies are not well described in the Korean population. We analyzed the cardiac anomalies and clinical features of Kabuki syndrome in a single tertiary center. Methods: A retrospective analysis was conducted for a total of 13 patients with Kabuki syndrome. Results: The median age at diagnosis of was 5.9 years (range, 9 days to 11 years and 8 months). All patients showed the characteristic facial dysmorphisms and congenital anomalies in multiple organs, and the diagnosis was delayed by 5.9 years (range, 9 days to 11 years and 5 months) after the first visit. Noncardiac anomalies were found in 84% of patients, and congenital heart diseases were found in 9 patients (69%). All 9 patients exhibited left-side heart anomalies, including hypoplastic left heart syndrome in 3, coarctation of the aorta in 4, aortic valve stenosis in 1, and mitral valve stenosis in 1. None had right-side heart disease or isolated septal defects. Genetic testing in 10 patients revealed 9 novel MLL2 mutations. All 11 patients who were available for follow-up exhibited developmental delays during the median 4 years (range, 9 days to 11 years 11 months) of follow-up. The leading cause of death was hypoplastic left heart syndrome. Conclusion: Pediatric cardiologist should recognize Kabuki syndrome and the high prevalence of left heart anomalies with Kabuki syndrome. Genetic testing can be helpful for early diagnosis and counseling.

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참고문헌

  1. Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T. Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 1981;99:565-9. https://doi.org/10.1016/S0022-3476(81)80255-7
  2. Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I. A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr 1981;99:570-3. https://doi.org/10.1016/S0022-3476(81)80256-9
  3. Niikawa N, Kuroki Y, Kajii T, Matsuura N, Ishikiriyama S, Tonoki H, et al. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet 1988;31:565-89. https://doi.org/10.1002/ajmg.1320310312
  4. Adam MP, Hudgins L. Kabuki syndrome: a review. Clin Genet 2005;67:209-19.
  5. Lee JH, Shim GH, Shin KS, Hong JY, Kim YW, Kim SH, et al. Congenital heart disease in Jeju: postnatal incidence and clinical features. Korean J Pediatr 2004;47:294-303.
  6. Botto LD, Correa A, Erickson JD. Racial and temporal variations in the prevalence of heart defects. Pediatrics 2001;107:E32. https://doi.org/10.1542/peds.107.3.e32
  7. Cheon CK, Sohn YB, Ko JM, Lee YJ, Song JS, Moon JW, et al. Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with Kabuki syndrome. J Hum Genet 2014;59: 321-5. https://doi.org/10.1038/jhg.2014.25
  8. Digilio MC, Marino B, Toscano A, Giannotti A, Dallapiccola B. Congenital heart defects in Kabuki syndrome. Am J Med Genet 2001;100:269-74. https://doi.org/10.1002/ajmg.1265
  9. McMahon CJ, Reardon W. The spectrum of congenital cardiac malformations encountered in six children with Kabuki syndrome. Cardiol Young 2006;16:30-3. https://doi.org/10.1017/S1047951105002052
  10. Hughes HE, Davies SJ. Coarctation of the aorta in Kabuki syndrome. Arch Dis Child 1994;70:512-4. https://doi.org/10.1136/adc.70.6.512
  11. Digilio MC, Baban A, Marino B, Dallapiccola B. Hypoplastic left heart syndrome in patients with Kabuki syndrome. Pediatr Cardiol 2010;31:1111-3. https://doi.org/10.1007/s00246-010-9773-y
  12. Armstrong L, Abd El Moneim A, Aleck K, Aughton DJ, Baumann C, Braddock SR, et al. Further delineation of Kabuki syndrome in 48 well-defined new individuals. Am J Med Genet A 2005;132A(3): 265-72. https://doi.org/10.1002/ajmg.a.30340
  13. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 2010;42:790-3. https://doi.org/10.1038/ng.646
  14. Micale L, Augello B, Maffeo C, Selicorni A, Zucchetti F, Fusco C, et al. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum Mutat 2014;35:841-50. https://doi.org/10.1002/humu.22547
  15. Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S, Ragge N, et al. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. Eur J Hum Genet 2012;20: 381-8. https://doi.org/10.1038/ejhg.2011.220
  16. Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, et al. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A 2013;161A:2234-43.
  17. Wan X, Liu L, Ding X, Zhou P, Yuan X, Zhou Z, et al. Mll2 controls cardiac lineage differentiation of mouse embryonic stem cells by promoting H3K4me3 deposition at cardiac-specific genes. Stem Cell Rev 2014;10:643-52. https://doi.org/10.1007/s12015-014-9527-y
  18. Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC, et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet 2012;90:119-24. https://doi.org/10.1016/j.ajhg.2011.11.021
  19. Banka S, Lederer D, Benoit V, Jenkins E, Howard E, Bunstone S, et al. Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2). Clin Genet 2015; 87:252-8. https://doi.org/10.1111/cge.12363
  20. Lindgren AM, Hoyos T, Talkowski ME, Hanscom C, Blumenthal I, Chiang C, et al. Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate. Hum Genet 2013;132:537-52. https://doi.org/10.1007/s00439-013-1263-x
  21. Lee S, Lee JW, Lee SK. UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program. Dev Cell 2012;22:25-37. https://doi.org/10.1016/j.devcel.2011.11.009
  22. Hemming S, Cakouros D, Isenmann S, Cooper L, Menicanin D, Zannettino A, et al. EZH2 and KDM6A act as an epigenetic switch to regulate mesenchymal stem cell lineage specification. Stem Cells 2014;32:802-15. https://doi.org/10.1002/stem.1573
  23. Marino B, Digilio MC. Congenital heart disease and genetic syndromes: specific correlation between cardiac phenotype and genotype. Cardiovasc Pathol 2000;9:303-15. https://doi.org/10.1016/S1054-8807(00)00050-8
  24. Rodriguez L, Diego-Alvarez D, Lorda-Sanchez I, Gallardo FL, Martinez-Fernandez ML, Arroyo-Mumoz ME, et al. A small and active ring X chromosome in a female with features of Kabuki syndrome. Am J Med Genet A 2008;146A:2816-21. https://doi.org/10.1002/ajmg.a.32521
  25. Chen CP, Lin SP, Tsai FJ, Chern SR, Wang W. Kabuki syndrome in a girl with mosaic 45,X/47,XXX and aortic coarctation. Fertil Steril 2008;89:1826.e5-7.
  26. Matsumoto N, Niikawa N. Kabuki make-up syndrome: a review. Am J Med Genet C Semin Med Genet 2003;117C:57-65. https://doi.org/10.1002/ajmg.c.10020

피인용 문헌

  1. Update on 13 Syndromes Affecting Craniofacial and Dental Structures vol.8, pp.None, 2015, https://doi.org/10.3389/fphys.2017.01038
  2. Congenital heart defects in molecularly proven Kabuki syndrome patients vol.173, pp.11, 2015, https://doi.org/10.1002/ajmg.a.38417
  3. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association vol.138, pp.21, 2015, https://doi.org/10.1161/cir.0000000000000606
  4. Loss of function of Kmt2d, a gene mutated in Kabuki syndrome, affects heart development in Xenopus laevis vol.248, pp.6, 2015, https://doi.org/10.1002/dvdy.39
  5. Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome vol.17, pp.9, 2015, https://doi.org/10.1371/journal.pbio.3000087
  6. Kabuki Syndrome-Clinical Review with Molecular Aspects vol.12, pp.4, 2015, https://doi.org/10.3390/genes12040468