Alagille syndrome
Authors:
T. Dědič 1; M. Jirsa 2; R. Kotalová 1
Authors‘ workplace:
Pediatrická klinika UK 2. LF a FN Motol, Praha, přednosta prof. MUDr. J. Lebl, CSc.
1; Laboratoř experimentální hepatologie IKEM, Prahavedoucí doc. MUDr. Mgr. M. Jirsa, CSc.
2
Published in:
Čes-slov Pediat 2014; 69 (4): 241-249.
Category:
Review
Overview
Alagille syndrome – AGS (OMIM 118450) is a highly variable multisystem autosomal dominant disorder with incomplete penetrance. The disease is caused by mutations in JAG1 or rarely in NOTCH2. Both genes encode extracellular signaling proteins involved in embryogenesis. Presence of pathogenic mutations leads to multiple malformations. AGS has extremely pleitropic clinical manifestations, even within the same family members carrying the same mutations. Consequentely, there is no correlation between genotype and phenotype.
Cholestatic liver disease due to bile duct paucity with high levels of cholesterol, formation of xanthomas and a rigorous pruritus, cardiovascular anomalies (most commonly peripheral pulmonary artery stenosis), “butterfly-like” vertebrae, ophtalmologic anomalies (posterior embrytoxon) and a typical craniofacial dysmorphia including triangular face, prominent forehead, saddle nose and narrow chin represent the key clinical features of AGS. Renal, vascular and other malformations are also frequent. Liver transplantation in childhood is necessary in cases with severe liver disease.
Key words:
Alagille syndrome, bile duct paucity, JAG1, neonatal cholestasis
Sources
1. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling cell fate control and signal integration in development. Science 1999; 284: 770–776.
2. Alagille D, Odièvre 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.
3. Kamath BM, Bason L, Piccoli DA, et al. Consequences of JAG1 mutations. J Med Genet 2003; 40: 891–895.
4. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997; 16: 243–251.
5. Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997; 16: 235–242.
6. McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am J Hum Genet 2006; 79: 169–173.
7. Warthen DM, Moore EC, Kamath BM, et al. Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum Mutat 2006; 27: 436–443.
8. Boyer J, Crosnier C, Driancourt C, et al. Expression of mutant JAGGED1 alleles in patients with Alagille syndrome. Human Genet 2005; 116: 445–453.
9. Morrissette JD, Colliton RP, Spinner NB. Defective intracelular transport and processing of JAG1 missence mutations in Alagille syndrome. Hum Mol Genet 2001; 10: 405–413.
10. Kamath BM, Bauer RC, Loomes KM, et al. NOTCH2 mutations in Alagille syndrome. J Med Genet A 2012; 49: 138–144.
11. Kamath BM, Spinner NB, Piccoli DA. Alagille syndrome. In: Suchy P (ed).: Liver Disease in Children. 3rd ed. New York: Cambridge University Press, 2007: 326–345.
12. Alagille D, Estrada A, Hadchouel M, et al. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 1987; 110: 195–200.
13. Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 1999; 29: 822–829.
14. Deprettere A, Portmann B, Mowat AP. Syndromic paucity of the intrahepatic bile ducts: diagnostic difficulty; severe morbidity throughout early childhood. J Pediatr Gastroenterol Nutr 1987; 6: 865–871.
15. Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Variable morbidity in Alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr 1999; 84: 56–60.
16. Hoffenberg EJ, Narkewizc MR, Sondheimer JM, et al. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995; 127: 220–224.
17. Kaye AJ, Rand EB, Munoz PS, et al. Effect of Kasai procedure on hepatic outcome in Alagille syndrome. J Pediatr Gastroenterol Nutr 2010; 51: 319–321.
18. Kaufmann SS, Wood RP, Shaw BW Jr, et al. Hepatocarcinoma in a child with the Alagille syndrome. Am J Dis Child 1987; 141: 698–700.
19. McElhinney DB, Krantz ID, Bason L, et al. Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome. Circulation 2002; 106: 2567–2574.
20. Watson GH, Miller V. Arterio-hepatic dysplasia. Familial pulmonary arterial stenosis with neonatal liver diseases. Arch Dis Child 1973; 48: 459–466.
21. Krantz ID, Smith R, Colliton RP, et al. Jagged1 mutations in patients ascertained with isolated congenital heart defects. Am J Med Genet 1999; 84: 56–60.
22. Bales CB, Kamath BM, Munoz PS, et al. Pathologic lower extremity fractures in children with Alagille syndrome. J Pediatr Gastroenterol Nutr 2010; 51: 66–70.
23. Hingorani M, Nischal KK, Davies A, et al. Ocular abnormalities in Alagille syndrome. Ophtalmology 1999; 106: 330–337.
24. Rennie CA, Chowdhury S, Khan J, et al. The prevalence and associated features of posterior embryotoxon in the general ophthalmic cloníc. Eye 2005; 19: 396–399.
25. Brodsky MC, Cunniff C. Ocular anomalies in the Alagille syndrome (arteriohepatic dysplasia). Ophthalmology 1993; 100: 1767–1774.
26. Kamath BM, Loomes KM, Oakey RJ, et al. Facial features in Alagille syndrome: Specific or Alagille syndrome. Am J Med Genet 2002; 112: 163–170.
27. Kamath BM, Spinner NB, Emerick KM, et al. Vascular anomalies in Alagille syndrome: significant cause of morbidity and mortality. Circulation 2004; 109: 1354–1358.
28. Woolfenden AR, Albers GW, Steinberg GK, et al. Moyamoya syndrome in children with Alagille syndrome: additional evidence of a vasculopathy. Pediatrics 1999; 103: 505–508.
29. Martin SR, Garel L, Alvarez F. Alagille´s syndrome associated with cystic renal disease. Arch Dis Child 1996; 74: 232–235.
30. Berard E, Sarles J, Triolo V, e al. Renovascular hypertension and vascular anomalies in Alagille syndrome. Pediatr Nephrol 1998; 12: 121–124.
31. Habib R, Dommergues JP, Gubler MC, et al. Glomerular mesangiolipidosis in Alagille syndrome. Pediatr Nephrol 1987; 1: 455–454.
32. Schonck M, Hoorntje S, van Hooff J. Renal transplantation in Alagille syndrome. Nephrol Dial Transplant 1998; 13: 197–199.
33. Olsen IE, Ittenbach RF, Rovner AJ, et al. Deficits in size-adjusted bone mass in children with Alagille syndrome. J Pediatr Gastroenterol Nutr 2005; 40: 76–82.
34. Bucuvalas JC, Horn JA, Carlsson L, et al. Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature. J Clin Endocrinol Metab 1993; 76: 1477–1482.
35. Kamath BM, Wanrong Y, Heather M, et al. Outcomes of liver transplantation for patients with Alagille syndrome: The studies of pediatric liver transplantation experience, Liver Transplantation 2012; 18: 940–948.
36. Chong SK, Lindridge J, Moniz C, Mowat AP. Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts. J Pediatr Gastroenterol Nutr 1989; 9: 445–449.
37. Kamath BM, Kathleen LM, Piccoli DA. Medical management of Alagille syndrome. J Pediatr Gastroenterol Nutr 2010; 50: 580–586.
38. Emerick KM, Whitington PF. Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome. Hepatology 2002; 35: 1501–1506.
Labels
Neonatology Paediatrics General practitioner for children and adolescentsArticle was published in
Czech-Slovak Pediatrics
2014 Issue 4
Most read in this issue
- Alagille syndrome
- Clinical and biochemical characteristics of Kawasaki syndrome in 22 children
- Drug induced aseptic meningitis and Lyell syndrome: Rare causes of headache and exanthema in adolescents
- Children´s involuntary exposure in smoking environment is even more dangerous than it has been expected