Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
권호 표지

Clinical manifestation and outcome of alagille syndrome in Korea: a study of 30 patients

Alagille 증후군 환아의 임상 양상과 장기 예후에 대한 연구

  • Shin, Jee Youn (Department of Pediatrics, Collage of Medicine, Seoul National University) ;
  • Kim, You Jeong (Department of Pediatrics, Collage of Medicine, Seoul National University) ;
  • Seo, Jeong Kee (Department of Pediatrics, Collage of Medicine, Seoul National University)
  • 신지연 (서울대학교 의과대학 소아과학교실) ;
  • 김유정 (서울대학교 의과대학 소아과학교실) ;
  • 서정기 (서울대학교 의과대학 소아과학교실)
  • Received : 2006.06.23
  • Accepted : 2006.08.18
  • Published : 2006.10.15
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose : The purpose of this study was to examine the clinical courses and long-term outcomes of children with Allagille syndrome in Korea, and to evaluate the prognostic potentials of identified variables. Methods : We reviewed the clinical manifestations and outcomes of 30 children with Alagille syndrome, investigated from 1984 to 2006 until the end of this study (defined as death or last visit; mean follow-up : 5 years). Results : Cholestasis occurred in 100 percent, cardiovascular abnormalities in 83.3 percent, butterfly vertebrae in 30.0 percent, posterior embryotoxon in 43.3 percent, and a characteristic facial appearance in 100 percent. At study conclusion, of these 30 patients, eight had died (26.7 percent); six related to Alagille syndrome. Five patients died of a liver disease complication. Liver transplantation was carried out in five of the 30 patients (16.7 percent) and one of these died due to hyperacute rejection. At age two, cholestasis improved in 17 of the 30 patients. Those who had severe cholestasis at 2 years of age tended to have a complication, such as liver cirrhosis or liver transplantation, or to have died. Conclusion : Hepatic complications account for the most mortalities in patients with Alagille syndrome. Careful and complete assessments should be made in children who have cholestasis at 2 years of age. Further investigations of more cases are required.

목 적 : Alagille 증후군에 대하여 국내 증례 보고가 된 바 있으나 국내 Alagille 증후군 환자의 임상 양상에 대한 종합적인 분석은 없는 실정이다. 이에 국내 Alagille 증후군 환자의 임상양상과 장기 예후, 예후에 미치는 요인에 대해 알아보고자 한다. 방 법 : 1984년 7월부터 2006년 5월까지 서울대학교병원 소아과를 방문하여 Alagille 증후군으로 진단받은 30명의 환자를 대상으로, 만성 쓸개즙정체, 심혈관계 질환, 척추 이상, 눈의 이상, 특징적 얼굴형, 검사 결과, 예후를 기록지를 통하여 후향적으로 검토하였다. 결 과 : 만성 쓸개즙정체를 보인 환자가 100%, 심혈관계 이상이 있는 환자가 84.4%, 골격계 이상이 있는 경우가 30.0%, 안구의 이상이 있는 경우가 43.3%, 특징적 얼굴형을 보이는 경우가 100%였다. 30례의 환자 가운데 17례는 2세 경에 만성 쓸개즙정체가 호전되었고, 13례는 2세 이후에도 만성 쓸개즙정체가 지속되었다. 2세 경에도 만성 쓸개즙정체가 지속되는 환자는 합병증의 빈도가 유의하게 높았다(P=0.001). 30례의 환자 가운데 Alagille 증후군으로 인한 사망이 6례였고 이중 5례가 간질환의 합병증으로 사망하였다. 결 론 : Alagille 증후군 환자에서 간질환의 합병증이 사망의 중요한 원인이 되므로 이에 대한 주의 깊은 추적 관찰이 필요하며, 2세경에도 만성 쓸개즙정체가 호전되지 않는 경우 간이식을 요하거나 사망하는 빈도가 높으므로, 2세경에도 만성 쓸개즙정체가 지속되면 간이식을 고려해야 할 것이다.

Keywords

References

  1. Watson GH, Miller V. Arteriohepatic dysplasia, familial pulmonary stenosis with neonatal liver disease. Arch Dis Child 1973;48:459-66 https://doi.org/10.1136/adc.48.6.459
  2. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur. J Pediatr 1975; 86:63-71 https://doi.org/10.1016/S0022-3476(75)80706-2
  3. Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia):review of 80 cases. J Pediatr 1987; 110:195-200 https://doi.org/10.1016/S0022-3476(87)80153-1
  4. Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet 1997;34:152-7 https://doi.org/10.1136/jmg.34.2.152
  5. Elmslie FV, Vivian AJ, Gardiner H, Hall C, Mowat AP, Winter RM. Alagille syndrome:family studies. J Med Genet 1995;32:264-8 https://doi.org/10.1136/jmg.32.4.264
  6. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients:Frequency and relation to prognosis. Hepatology 1999;29:822-9 https://doi.org/10.1002/hep.510290331
  7. Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Hall TR, et al. Variable Morbidity in Alagille Syndrome: A Review of 43 Cases. J Pediatr Gastroenterol Nutr 1999;29:431-7 https://doi.org/10.1097/00005176-199910000-00011
  8. Piccoli DA, Spinner NB. Alagille syndrome and the Jagged1 gene. Semin Liver Dis 2001;21:525-34 https://doi.org/10.1055/s-2001-19036
  9. Subramaniam P, Kniseley A, Mieli-Vergani G, Baker A. Alagille syndrome - The difficulty of initial diagnosis:PH 1-21[Abstract]. J Pediatr Gastroenterol Nutr 2005;40:676
  10. Li L, Krantz ID, Deng. Y, Genin A, Banta AB, Collins CC, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997;16:243-51 https://doi.org/10.1038/ng0797-243
  11. Spinner NB, Colliton RP, Crosnier C, Krantz ID, Hadchouel M, Meunier-Rotival M. Jagged1 mutations in Alagille syndrome. Hum Mutat 2001;17:18-33 https://doi.org/10.1002/1098-1004(2001)17:1<18::AID-HUMU3>3.0.CO;2-T
  12. Han HS, Lim SH, Kim YS, Seo JK, Moon HR. Two Case of Watson-Alagille Syndrome. J Korean Pediatr Soc 1985; 28:1047-51
  13. Bom EK, Kim DH, Koh DH, Choi YY, Ma JS, Hwang TJ. Three cases of Watson-Alagille syndrome. J Korean Pedatr Soc 1991;34:1699-706
  14. Hwang EK, Lee GH, Ryoo E, Cho KH, Kim GH, Lee HS, et al. A case of Alagille syndrome. J Korean Pediatr Soc 1998;41:410-4
  15. Kamath BM, Gason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. J Med Genet 2003;40: 891-5 https://doi.org/10.1136/jmg.40.12.891
  16. Warthen DM, Moore EC, Kamath BM, Morrissette JJD, Sanchez P, Piccoli DA, et al. Jagged1(JAG1) Mutations in Alagille Syndrome:Increasing the Mutation Detection Rate. Hum Mut 2006;27:436-43 https://doi.org/10.1002/humu.20310
  17. Riely CA, Cotlier E, Jensen PS, Klatskin G. Arteriohepatic dysplasia:a benign syndrome of intrahepatic cholestasis with multiple organ involvement. Ann Internal Med 1979; 91:520-7 https://doi.org/10.7326/0003-4819-91-4-520
  18. Rabinovitz M, Imperial JC, Schade RR, Van Thiel DH. Hepatocelluar carcinoma in Alagille's syndrome:a family study. J Pediatr Gastroenterol Nutr 1978;8:26-30 https://doi.org/10.1097/00005176-198901000-00006
  19. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome:a study of 163 patients. Gut 2001;49:431-43 https://doi.org/10.1136/gut.49.3.431
  20. Yuan ZR, Okaniwa M, Nagata I, Tazawa Y, Ito M, Kawarazaki H, et al. The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome. Clin Genet 2001;59:330-7 https://doi.org/10.1034/j.1399-0004.2001.590506.x